Phenotypes associated with this allele

• Allele Symbol: Tlr4^Lps-d
• Allele Name: defective lipopolysaccharide response
• Allele ID: MGI:1857718
• Summary: 8 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Tlr4^Lps-d/Tlr4^Lps-d	B6.C3-Tlr4^Lps-d	MGI:4412003
hm2	Tlr4^Lps-d/Tlr4^Lps-d	C3H/HeJ-Tlr4^Lps-d	MGI:3706990
hm3	Tlr4^Lps-d/Tlr4^Lps-d	C.C3-Tlr4^Lps-d/J	MGI:3690970
hm4	Tlr4^Lps-d/Tlr4^Lps-d	involves: C3H/HeJ	MGI:3588645
cx5	Cd14^tm1Smg/Cd14^tm1Smg Tlr4^Lps-d/Tlr4^Lps-d	C3.129S1-CD14^tm1Smg	MGI:3834574
cx6	Tlr2^tm1Kir/Tlr2^tm1Kir Tlr4^Lps-d/Tlr4^Lps-d	C3.Cg-Tlr2^tm1Kir Tlr4^Lps-d	MGI:3706988
cx7	ru2l/ru2l Tlr4^Lps-d/Tlr4^Lps-d	C.C3 Tlr4^Lps-d/J-ru2l/GrsrJ	MGI:3718232
cx8	Tlr4^Lps-d/Tlr4^Lps-d Tg(IghelMD4)4Ccg/0 Tg(KLK4mHEL)6Ccg/0	involves: 129P2/OlaHsd * C3H/HeJ * C57BL/6	MGI:3694809

Genotype
MGI:4412003

hm1

• Allelic Composition: Tlr4^Lps-d/Tlr4^Lps-d
• Genetic Background: B6.C3-Tlr4^Lps-d

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

cardiovascular system

abnormal artery morphology ( J:101995 )

• no increase in thickness of external elastic lamina after treatment with lipopolysaccharide

• no increase in external elastic lamina of contralateral carlotid arteries after 28 days of carotid artery ligation

• no increase in area of the media

atherosclerotic lesions ( J:101995 )

• larger plaques made up of smooth muscle and foam cells when treated with lipopolysaccharide and on a high fat diet

abnormal vascular wound healing ( J:101995 )

• increased neointimal formation but not to the extent seen in controls after lipopolysaccharide treatment

• no correlation between external elastic lamina area and neointimal area as is seen in controls

homeostasis/metabolism

abnormal vascular wound healing ( J:101995 )

• increased neointimal formation but not to the extent seen in controls after lipopolysaccharide treatment

• no correlation between external elastic lamina area and neointimal area as is seen in controls

Genotype
MGI:3706990

hm2

• Allelic Composition: Tlr4^Lps-d/Tlr4^Lps-d
• Genetic Background: C3H/HeJ-Tlr4^Lps-d

mortality/aging

increased susceptibility to Poxviridae infection induced morbidity/mortality ( J:162716 )

• 10 days after intranasal infection with 5 x 10⁵ pfu Vac-GFL 70% of mice succumb unlike wild-type controls that all survive

decreased susceptibility to induced morbidity/mortality ( J:121930 )

• bacterial lipoteichoic acid exposure after priming by IFNgamma and sensitization with D-galactosamine induces lethal shock in Tlr4-deficient mutants, while Tlr2- and Tlr2/4-doubly deficient mice are protected

• systemic challenge with Myr₃-CSK₄ (a synthetic lipopeptide) after D-galactosamine induces lethal shock in wild-type mice, but mutants are protected

• heat-inactivated E. coli exposure results in fatal toxemia as in wild-type mice

growth/size/body

decreased susceptibility to weight loss ( J:162716 )

• reduced weight loss following infection with Vac-GFL

decreased body size ( J:118467 )

• always smaller than controls

decreased body weight ( J:126488 )

• lower body weight than controls after 8 weeks on a high fat diet

• weights are 15% lower than controls after 8 months on a high fat diet

• food intake comparable to controls

enlarged lung ( J:114985 )

• significantly increased lung volume at 3 months of age in contrast to normal body weights through 12 months

immune system

immune system phenotype ( J:209808 )

N • mice inoculated with Candida albicans show vaginal fungal burden and polymorphonuclear neutrophil migration to the vagina that are similar to that seen in wild-type mice

abnormal macrophage chemotaxis ( J:122597 )

• robust macrophage response at the site of spinal injury

abnormal phagocyte morphology ( J:125179 )

• phagocytes fail to respond to LPS stimulation

• however, response to stimulation with TLR9 or TLR7 and TLR8 with their ligands (CpG and R848, respectively) is similar to in wild-type cells

abnormal spleen weight ( J:37271 )

• spleen weight fails to increase with dextran sodium sulfate treatment as it does in controls

abnormal microglial cell physiology ( J:99051 )

• resistant to lipopolysaccharide induced apoptosis

abnormal cytokine level ( J:96680 )

• keratinocyte derived cytokine levels in lungs are unaffected by lipopolysaccharide

• macrophage inflammatory protein-2 levels in lungs are unaffected by lipopolysaccharide

abnormal interleukin level ( J:96680 )

• Il-6 levels in lungs are unaffected by lipopolysaccharide

• il6 levels increase less on a high fat diet than in controls

increased circulating interleukin-6 level ( J:37271 )

• increased levels after 7 days of dextran sodium sulfate treatment

abnormal tumor necrosis factor level ( J:96680 )

• TNF alpha levels in lungs are unaffected by lipopolysaccharide

• less increase in TNF alpha on a high fat diet than in controls

liver inflammation ( J:135830 )

• after BDL, necroinflammatory foci and lymphocytic infiltration are obviously less than in controls

lung inflammation ( J:96680 )

• no increase in white blood cells or neutrophiles in bronchoalveolar fluid

• white blood cells and neutrophiles are not detected by myeloperoxidase assay

abnormal susceptibility to infection ( J:162716 )

• following intranasal infection with 1x10⁴ pfu Vac-GFL (a recombinant vaccinia virus that expresses a reporter protein) weight loss is reduced at 1 - 3 and 7 - 8 days after infection but the decrease in body temperature is more severe at 4 - 7 days afteinfection and viral replication is increased

increased susceptibility to Poxviridae infection induced morbidity/mortality ( J:162716 )

• 10 days after intranasal infection with 5 x 10⁵ pfu Vac-GFL 70% of mice succumb unlike wild-type controls that all survive

hematopoietic system

hematopoietic system phenotype ( J:135830 )

N • B cell apoptosis in Peyer's patch is not observed after bile duct ligation (BDL)

abnormal macrophage chemotaxis ( J:122597 )

• robust macrophage response at the site of spinal injury

abnormal phagocyte morphology ( J:125179 )

• phagocytes fail to respond to LPS stimulation

• however, response to stimulation with TLR9 or TLR7 and TLR8 with their ligands (CpG and R848, respectively) is similar to in wild-type cells

abnormal spleen weight ( J:37271 )

• spleen weight fails to increase with dextran sodium sulfate treatment as it does in controls

abnormal microglial cell physiology ( J:99051 )

• resistant to lipopolysaccharide induced apoptosis

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:135830 )

N • after BDL, serum alanine transaminase levels are not different from controls

abnormal circulating leptin level ( J:126488 )

• increase in blood leptin on a high fat diet is 36% less than in controls

decreased body temperature ( J:162716 )

• more severe reduction in body temperature following infection with Vac-GFL

pulmonary edema ( J:96680 )

• resistant to lipopolysaccharide induced lung interstitial edema

• less protein leakage into bronchoalveolar lavage fluid after lipopolysaccharide inhalation

abnormal gas homeostasis ( J:126488 )

increased oxygen consumption ( J:126488 )

• oxygen consumption is higher after 8 weeks on a high fat diet than controls

decreased respiratory quotient ( J:126488 )

• lower respiratory exchange ratio

abnormal glucose homeostasis ( J:126488 )

abnormal circulating glucose level ( J:126488 )

• faster disappearance of glucose in response to insulin when on a high fat diet

decreased circulating insulin level ( J:126488 )

• lower blood insulin levels when on a high fat diet

improved glucose tolerance ( J:126488 )

• lower blood glucose in a glucose tolerance test when on a high fat diet

increased adiponectin level ( J:126488 )

• levels remain elevated on a high fat diet

abnormal lipid level ( J:126488 )

abnormal fatty acids level ( J:126488 )

• less elevated than for controls on a high fat diet

decreased liver triglyceride level ( J:126488 )

• less increase in hepatic triglycerides on a high fat diet than in controls

abnormal cytokine level ( J:96680 )

• keratinocyte derived cytokine levels in lungs are unaffected by lipopolysaccharide

• macrophage inflammatory protein-2 levels in lungs are unaffected by lipopolysaccharide

abnormal interleukin level ( J:96680 )

• Il-6 levels in lungs are unaffected by lipopolysaccharide

• il6 levels increase less on a high fat diet than in controls

increased circulating interleukin-6 level ( J:37271 )

• increased levels after 7 days of dextran sodium sulfate treatment

abnormal tumor necrosis factor level ( J:96680 )

• TNF alpha levels in lungs are unaffected by lipopolysaccharide

• less increase in TNF alpha on a high fat diet than in controls

decreased susceptibility to ischemic brain injury ( J:117223 )

• reduced brain edema after cerebral ischemia/reperfusion

• less inflammation after cerebral ischemia/reperfusion

• less nerve cell swelling after cerebral ischemia/reperfusion

• reduced neurological impairment after cerebral ischemia/reperfusion

decreased cerebral infarct size ( J:117223 , J:124100 )

• infarctions due to cerebral ischemia/reperfusion are smaller in size (J:117223)

• damage due to middle cerebral artery occlusion is considerably reduced (J:124100)

liver/biliary system

decreased liver triglyceride level ( J:126488 )

• less increase in hepatic triglycerides on a high fat diet than in controls

abnormal hepatocyte morphology ( J:135830 )

• confluent foci of feathery hepatocyte degeneration due to bile acid cytotoxicity are significantly reduced compared to controls 24 hours after BDL

focal hepatic necrosis ( J:135830 )

abnormal liver physiology ( J:98036 )

• liver protected from ischemia/reperfusion injury

decreased hepatocyte apoptosis ( J:135830 )

• hepatocyte cell death is reduced compared to controls after BDL

liver inflammation ( J:135830 )

• after BDL, necroinflammatory foci and lymphocytic infiltration are obviously less than in controls

adipose tissue

decreased fat cell size ( J:126488 )

• adipocyte size reduced 30% relative to controls on a high fat diet

• reduced aggregation of macrophage around dying adipocytes than in controls

decreased epididymal fat pad weight ( J:126488 )

• reduced 40% compared to controls when on a high fat diet

• weight similar to controls on a normal diet

decreased percent body fat/body weight ( J:118467 )

• 70% less body fat

cardiovascular system

rectal hemorrhage ( J:37271 )

• rectal bleeding after 7 days of dextrose sodium sulfate treatment is reduced relative to controls

• recover from bleeding after 10 days of treatment when 50% of controls are dead

digestive/alimentary system

rectal hemorrhage ( J:37271 )

• rectal bleeding after 7 days of dextrose sodium sulfate treatment is reduced relative to controls

• recover from bleeding after 10 days of treatment when 50% of controls are dead

respiratory system

abnormal respiratory system morphology ( J:114985 )

enlarged lung ( J:114985 )

• significantly increased lung volume at 3 months of age in contrast to normal body weights through 12 months

pulmonary edema ( J:96680 )

• resistant to lipopolysaccharide induced lung interstitial edema

• less protein leakage into bronchoalveolar lavage fluid after lipopolysaccharide inhalation

dilated pulmonary alveolar duct ( J:114985 )

• enlarged air spaces distal to the terminal bronchioles

abnormal pulmonary alveolus morphology ( J:114985 )

• destruction of normal alveolar structures

abnormal respiratory system physiology ( J:96680 )

lung inflammation ( J:96680 )

• no increase in white blood cells or neutrophiles in bronchoalveolar fluid

• white blood cells and neutrophiles are not detected by myeloperoxidase assay

nervous system

decreased neuron apoptosis ( J:124100 )

• neurons are resistant to apoptosis caused by glucose deficiency

abnormal microglial cell physiology ( J:99051 )

• resistant to lipopolysaccharide induced apoptosis

decreased susceptibility to ischemic brain injury ( J:117223 )

• reduced brain edema after cerebral ischemia/reperfusion

• less inflammation after cerebral ischemia/reperfusion

• less nerve cell swelling after cerebral ischemia/reperfusion

• reduced neurological impairment after cerebral ischemia/reperfusion

decreased cerebral infarct size ( J:117223 , J:124100 )

• infarctions due to cerebral ischemia/reperfusion are smaller in size (J:117223)

• damage due to middle cerebral artery occlusion is considerably reduced (J:124100)

abnormal nervous system morphology ( J:124100 )

abnormal myelin sheath morphology ( J:122597 )

• increased myelin destruction at site of spinal cord injury

• no clear delineation between injured and spared tissues

behavior/neurological

abnormal motor coordination/balance ( J:122597 )

• impaired recovery of fore-limb-hindlimb coordination as measured 4-6 weeks after spinal cord injury

abnormal locomotor behavior ( J:122597 )

• locomotor recovery impaired as measured 4-6 weeks after spinal cord injury

skeleton

increased bone mineral content ( J:118467 )

• greater mineral content

increased bone mineral density ( J:118467 )

• significantly increased bone mineral density at 20 weeks

• density continues to increase over time

increased bone mass ( J:118467 )

• increased bone area of the tibia

decreased susceptibility to bone fracture ( J:118467 )

• bones resistant to fracture

muscle

abnormal muscle cell glucose uptake ( J:126488 )

• insulin stimulated glucose uptake by soleus muscle is not affected by palmitate treatment or by other fatty acids

cellular

decreased neuron apoptosis ( J:124100 )

• neurons are resistant to apoptosis caused by glucose deficiency

decreased hepatocyte apoptosis ( J:135830 )

• hepatocyte cell death is reduced compared to controls after BDL

abnormal macrophage chemotaxis ( J:122597 )

• robust macrophage response at the site of spinal injury

abnormal muscle cell glucose uptake ( J:126488 )

• insulin stimulated glucose uptake by soleus muscle is not affected by palmitate treatment or by other fatty acids

Genotype
MGI:3690970

hm3

• Allelic Composition: Tlr4^Lps-d/Tlr4^Lps-d
• Genetic Background: C.C3-Tlr4^Lps-d/J

cardiovascular system

decreased angiogenesis ( J:171028 )

• perfusion restoration is significantly reduced 7 days after femoral artery ligation

decreased response of heart to induced stress ( J:106358 )

• exhibit reduced cardiac hypertrophy following pressure overload compared to controls

• exhibit no significant myocardial interstitial fibrosis or cardiac myocyte death following pressure overload unlike wild-type

homeostasis/metabolism

decreased response of heart to induced stress ( J:106358 )

• exhibit reduced cardiac hypertrophy following pressure overload compared to controls

• exhibit no significant myocardial interstitial fibrosis or cardiac myocyte death following pressure overload unlike wild-type

skeleton

abnormal bone structure ( J:118467 )

increased bone mineral content ( J:118467 )

• greater mineral content but not yet significant at 6 weeks

increased bone mineral density ( J:118467 )

• significantly increased bone mineral density at 20 weeks

• density continues to increase over time

increased bone mass ( J:118467 )

• increased bone area of the tibia

Genotype
MGI:3588645

hm4

• Allelic Composition: Tlr4^Lps-d/Tlr4^Lps-d
• Genetic Background: involves: C3H/HeJ

immune system

abnormal osteoclast differentiation ( J:131353 )

• lipopolysaccharide fails to inhibit RANKL induced osteoclast formation as it does in controls

• antibody to IFN-beta or to IFNAR1 reverses inhibition of osteoclast formation induced by RANKL

abnormal T-helper 2 physiology ( J:96356 )

• Th2 responses elevated after induction of autoimmune arthritis

abnormal tumor necrosis factor level ( J:114368 , J:124334 )

• diminished TNF alpha expression after 90 minutes of liver ischemia followed by 6 hours of reperfusion (J:114368)

• macrophage primary but not secondary necrotic cells with residual stimulatory affect on TNF alpha production by macrophage (J:124334)

increased susceptibility to induced arthritis ( J:96356 )

• reduced susceptibility to arthritis induced by type II collagen

increased susceptibility to bacterial infection ( J:5721 , J:51522 , J:87807 )

• low responsiveness of spleen cells to lipopolysaccharides (J:5721)

• increased sensitivity to gram (-) infection (J:51522)

• significantly shortened survival after infection with Klebsiella pneumoniae (J:87807)

• increased K. pneumoniae levels in the lung (J:87807)

behavior/neurological

hyporesponsive to tactile stimuli ( J:97819 )

• reduced mechanical allodynia after nerve injury

increased thermal nociceptive threshold ( J:97819 )

• attenuated response to heat

skeleton

abnormal osteoclast differentiation ( J:131353 )

• lipopolysaccharide fails to inhibit RANKL induced osteoclast formation as it does in controls

• antibody to IFN-beta or to IFNAR1 reverses inhibition of osteoclast formation induced by RANKL

increased susceptibility to induced arthritis ( J:96356 )

• reduced susceptibility to arthritis induced by type II collagen

muscle

muscle phenotype ( J:116310 )

N • MCP-1 (monocyte chemoattractant protein-1) release from isolated mouse aorta smooth muscle cells (MAoSMC) by stimulation with dsRNA is normal relative to controls

nervous system

abnormal glial cell apoptosis ( J:99051 )

• isolated microglia exposed to LPS are resistant to apoptosis

homeostasis/metabolism

abnormal circulating enzyme level ( J:114368 )

• myeloperoxidase levels are reduced after 90 minutes of liver ischemia followed by 6 hours of reperfusion

• increased HO-1 expression

decreased circulating alanine transaminase level ( J:114368 )

• serum levels decreased after 90 minutes of liver ischemia followed by 6 hours of reperfusion

abnormal tumor necrosis factor level ( J:114368 , J:124334 )

• diminished TNF alpha expression after 90 minutes of liver ischemia followed by 6 hours of reperfusion (J:114368)

• macrophage primary but not secondary necrotic cells with residual stimulatory affect on TNF alpha production by macrophage (J:124334)

hematopoietic system

abnormal osteoclast differentiation ( J:131353 )

• lipopolysaccharide fails to inhibit RANKL induced osteoclast formation as it does in controls

• antibody to IFN-beta or to IFNAR1 reverses inhibition of osteoclast formation induced by RANKL

abnormal T-helper 2 physiology ( J:96356 )

• Th2 responses elevated after induction of autoimmune arthritis

cellular

abnormal glial cell apoptosis ( J:99051 )

• isolated microglia exposed to LPS are resistant to apoptosis

abnormal osteoclast differentiation ( J:131353 )

• lipopolysaccharide fails to inhibit RANKL induced osteoclast formation as it does in controls

• antibody to IFN-beta or to IFNAR1 reverses inhibition of osteoclast formation induced by RANKL

hearing/vestibular/ear

hearing/vestibular/ear phenotype ( J:168789 )

N • cisplatin and lipopolysaccharide treatment does not lead to significant increases in auditory brainstem response as is observed in controls

Genotype
MGI:3834574

cx5

• Allelic Composition: Cd14^tm1Smg/Cd14^tm1Smg; Tlr4^Lps-d/Tlr4^Lps-d
• Genetic Background: C3.129S1-CD14^tm1Smg

immune system

abnormal macrophage physiology ( J:116691 )

• macrophages fail to respond to LPS even at the very high doses that stimulate macrophages homozygote for just the CD14^tm1Smg null allele

decreased tumor necrosis factor secretion ( J:116691 )

• no TNF is produced by macrophages in response to LPS stimulation

hematopoietic system

abnormal macrophage physiology ( J:116691 )

• macrophages fail to respond to LPS even at the very high doses that stimulate macrophages homozygote for just the CD14^tm1Smg null allele

Genotype
MGI:3706988

cx6

• Allelic Composition: Tlr2^tm1Kir/Tlr2^tm1Kir; Tlr4^Lps-d/Tlr4^Lps-d
• Genetic Background: C3.Cg-Tlr2^tm1Kir Tlr4^Lps-d

mortality/aging

decreased susceptibility to induced morbidity/mortality ( J:121930 )

• after sensitization with D-galactosamine, 150 ug of Salmonella LPS does not cause lethal toxemia in double mutants, while all Tlr2-deficient single mutants die

• double mutants are protected from bacterial lipoteichoic acid exposure after priming by IFNgamma and sensitization with D-galactosamine, while Tlr4-deficient mice and wild-type are susceptible to lethal shock by this treatment

• systemic challenge with Myr₃-CSK₄ (a synthetic lipopeptide) after D-galactosamine induces lethal shock in wild-type mice, but mutants are protected

immune system

abnormal macrophage physiology ( J:121930 )

• high dose stimulation of macrophages by Pam₃-CSK₄ does not induce activation of the macrophages in contrast to activation of Tlr2-deficient macrophages

• priming with IFNgamma does not allow activation of macrophages upon stimulation by Pam₃-CSK₄

hematopoietic system

abnormal macrophage physiology ( J:121930 )

• high dose stimulation of macrophages by Pam₃-CSK₄ does not induce activation of the macrophages in contrast to activation of Tlr2-deficient macrophages

• priming with IFNgamma does not allow activation of macrophages upon stimulation by Pam₃-CSK₄

Genotype
MGI:3718232

cx7

• Allelic Composition: ru2l/ru2l; Tlr4^Lps-d/Tlr4^Lps-d
• Genetic Background: C.C3 Tlr4^Lps-d/J-ru2l/GrsrJ

ru2l/ru2l Tlr4^Lps-d/Tlr4^Lps-d with littermate control

pigmentation

diluted coat color ( J:123265 )

decreased tail pigmentation ( J:123265 )

• the dark pigment of the tail is diluted to a pink color

decreased eye pigmentation ( J:123265 )

• dark red eyes at weaning become lighter red in color with age

vision/eye

decreased eye pigmentation ( J:123265 )

• dark red eyes at weaning become lighter red in color with age

limbs/digits/tail

decreased tail pigmentation ( J:123265 )

• the dark pigment of the tail is diluted to a pink color

reproductive system

reproductive system phenotype ( J:123265 )

N • normal fertility

integument

diluted coat color ( J:123265 )

decreased tail pigmentation ( J:123265 )

• the dark pigment of the tail is diluted to a pink color

Genotype
MGI:3694809

cx8

• Allelic Composition: Tlr4^Lps-d/Tlr4^Lps-d; Tg(IghelMD4)4Ccg/0; Tg(KLK4mHEL)6Ccg/0
• Genetic Background: involves: 129P2/OlaHsd * C3H/HeJ * C57BL/6

hematopoietic system

increased B-1 B cell number ( J:115059 )

• more B1 cells are detected among peritoneal lymphocytes in double transgenic mutants compared to Tg(IghelMD4)4Ccg single transgenic mutants

decreased B cell number ( J:115059 )

• a 35% reduction in number of recirculating mature autoreactive B cells is observed, compared to wild-type

immune system

increased B-1 B cell number ( J:115059 )

• more B1 cells are detected among peritoneal lymphocytes in double transgenic mutants compared to Tg(IghelMD4)4Ccg single transgenic mutants

decreased B cell number ( J:115059 )

• a 35% reduction in number of recirculating mature autoreactive B cells is observed, compared to wild-type