Phenotypes associated with this allele

• Allele Symbol: Tlr4^tm1Aki
• Allele Name: targeted mutation 1, Shizuo Akira
• Allele ID: MGI:1860885
• Summary: 13 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Tlr4^tm1Aki/Tlr4^tm1Aki	B6.129P2-Tlr4^tm1Aki	MGI:3706992
hm2	Tlr4^tm1Aki/Tlr4^tm1Aki	C.129P2-Tlr4^tm1Aki	MGI:5297119
hm3	Tlr4^tm1Aki/Tlr4^tm1Aki	involves: 129P2/OlaHsd	MGI:3588775
hm4	Tlr4^tm1Aki/Tlr4^tm1Aki	involves: 129P2/OlaHsd * C57BL/6	MGI:3665469
hm5	Tlr4^tm1Aki/Tlr4^tm1Aki	involves: 129P2/OlaHsd * C57BL/6J	MGI:3588776
ht6	Tlr4^tm1Aki/Tlr4^lps-2J	involves: 129P2/OlaHsd * C57BL/6 * DBA/2J	MGI:3629223
cn7	Stat3^tm2Aki/Stat3^tm2Aki Tlr4^tm1Aki/Tlr4^tm1Aki Lyz2^tm1(cre)Ifo/Lyz2^+	involves: 129P2/OlaHsd * C57BL/6	MGI:3771394
cx8	Tlr2^tm1Aki/Tlr2^tm1Aki Tlr4^tm1Aki/Tlr4^tm1Aki	B6.129P2-Tlr2^tm1Aki Tlr4^tm1Aki	MGI:3625114
cx9	Tlr2^tm1Kir/Tlr2^tm1Kir Tlr4^tm1Aki/Tlr4^tm1Aki	B6.129-Tlr2^tm1Kir Tlr4^tm1Aki	MGI:3706993
cx10	Tlr4^tm1Aki/Tlr4^tm1Aki Tlr5^tm1Flv/Tlr5^tm1Flv	involves: 129P2/OlaHsd * 129S1/Sv * C57BL/6	MGI:3665470
cx11	Npc1^m1N/Npc1^m1N Tlr4^tm1Aki/Tlr4^tm1Aki	involves: 129P2/OlaHsd * BALB/c	MGI:3706954
cx12	Apoe^tm1Unc/Apoe^tm1Unc Tlr4^tm1Aki/Tlr4^tm1Aki	involves: 129P2/OlaHsd * C57BL/6	MGI:3588777
cx13	Tlr2^tm1Aki/Tlr2^tm1Aki Tlr4^tm1Aki/Tlr4^tm1Aki	involves: 129P2/OlaHsd * C57BL/6	MGI:3707238

Genotype
MGI:3706992

hm1

• Allelic Composition: Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: B6.129P2-Tlr4^tm1Aki

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

mortality/aging

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

• mice are resistant to lethal shock induced by a synthetic lipopeptide analogue (Myr3CSK4)

respiratory system

respiratory system phenotype ( J:114985 )

N • no significant increase in inflammatory cells in the lungs over time

abnormal respiratory system morphology ( J:114985 )

• increased apoptosis in lungs

enlarged lung ( J:114985 )

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

abnormal pulmonary alveolar duct morphology ( J:114985 )

• enlarged air spaces distal to the terminal bronchioles

abnormal pulmonary alveolus morphology ( J:114985 )

• destruction of normal alveolar structures

abnormal pulmonary elastic fiber morphology ( J:114985 )

• elastin fibers are thin and fragmented in the lung parenchyma

• reduced elastase inhibitory activity in serum and in bronchoalveolar lavage fluid

abnormal respiratory system physiology ( J:147534 )

• bronchoalveolar protein levels are increased by ozone exposure

• ozone induced increase in bronchoalveolar cell counts is less than in controls at 3 hours but not 24 hours

abnormal airway responsiveness ( J:147534 )

• ozone exposure does not lead to hyperresponsiveness

increased lung compliance ( J:114985 )

• increased lung compliance

homeostasis/metabolism

decreased incidence of tumors by chemical induction ( J:135620 )

• azoxymethane and dextran sodium sulfate treatment to induce tumor formation

• no visible polyploid lesions are seen in the intestine as they are in controls

• only 5 of 18 mice have 1-2 small, flat dysplastic lesions compared to all controls having from 1 to 17 lesions, half of which are polyploid

decreased susceptibility to kidney reperfusion injury ( J:143920 )

• reduced ischemia/reperfusion injury as indicated by a lower rise in serum urea and creatinine 1 day after injury

neoplasm

decreased incidence of tumors by chemical induction ( J:135620 )

• azoxymethane and dextran sodium sulfate treatment to induce tumor formation

• no visible polyploid lesions are seen in the intestine as they are in controls

• only 5 of 18 mice have 1-2 small, flat dysplastic lesions compared to all controls having from 1 to 17 lesions, half of which are polyploid

digestive/alimentary system

digestive/alimentary phenotype ( J:135620 )

N • level of colitis developed after azoxymethane and dextran sodium sulfate treatment is similar to controls

renal/urinary system

decreased susceptibility to kidney reperfusion injury ( J:143920 )

• reduced ischemia/reperfusion injury as indicated by a lower rise in serum urea and creatinine 1 day after injury

abnormal nephron morphology ( J:143920 )

abnormal renal tubule morphology ( J:143920 )

abnormal renal tubule epithelium morphology ( J:143920 )

• fewer apoptotic tubular epithelial cells after ischemia/reperfusion injury as compared to controls except at 5 days after injury when apoptosis is elevated

• tubular epithelial cell proliferation is reduced 10 days after injury relative to controls

abnormal proximal convoluted tubule brush border morphology ( J:143920 )

• less brush border loss after ischemia/reperfusion injury as compared to controls

dilated renal tubule ( J:143920 )

renal tubular necrosis ( J:143920 )

• reduced tubular necrosis after ischemia/reperfusion injury as compared to controls

renal cast ( J:143920 )

• less cast formation after ischemia/reperfusion injury as compared to controls

growth/size/body

enlarged lung ( J:114985 )

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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
pulmonary emphysema		DOID:9675	OMIM:130700	J:114985

Genotype
MGI:5297119

hm2

• Allelic Composition: Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: C.129P2-Tlr4^tm1Aki

immune system

decreased susceptibility to induced arthritis ( J:178054 )

• in response to peptidoglycan or muramyl dipeptide (MDP), mice fail to develop arthritis unlike similarly treated wild-type mice

skeleton

decreased susceptibility to induced arthritis ( J:178054 )

• in response to peptidoglycan or muramyl dipeptide (MDP), mice fail to develop arthritis unlike similarly treated wild-type mice

Genotype
MGI:3588775

hm3

• Allelic Composition: Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd

immune system

decreased circulating interleukin-6 level ( J:145306 )

• following exposure to acid-induced acute lung injury, LPS, or 1-palmitoyl-2-arachidonoyl-phosphatidylcholine

increased susceptibility to bacterial infection ( J:53519 )

• reduced responsiveness to endotoxin (LPS)

decreased susceptibility to Orthomyxoviridae infection ( J:145306 )

• following exposure to inactivated H5N1 virus , acute-lung injury and IL6 production are attenuated compared to in wild-type mice

homeostasis/metabolism

decreased circulating interleukin-6 level ( J:145306 )

• following exposure to acid-induced acute lung injury, LPS, or 1-palmitoyl-2-arachidonoyl-phosphatidylcholine

decreased susceptibility to injury ( J:145306 )

• following exposure to acid-induced acute lung injury, mice exhibit alleviated symptoms compared to wild-type mice with decreased changes in elastance, edema, and serum IL6 levels

• following exposure to 1-palmitoyl-2-arachidonoyl-phosphatidylcholine, lung function is improved and IL6 production is decreased compared to in similarly treated wild-type mice

Genotype
MGI:3665469

hm4

• Allelic Composition: Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

immune system

decreased B cell proliferation ( J:76115 )

• unlike wild-type splenocytes, mutant B cells fail to exhibit a proliferative response to various concentrations of S. minnesota LPS

abnormal macrophage physiology ( J:76115 )

• in culture, mutant thioglycollate-elicited peritoneal macrophages fail to produce any detectable levels of IL-6 and TNF in response to 1 ng/ml of Salmonella minnesota (Re-595) LPS or synthetic E. coli-type lipid A, even in the presence of IFN-gamma

• mutant thioglycollate-elicited peritoneal macrophages fail to produce any NO₂^- in response to S. minnesota LPS or lipid A, even in the presence of IFN-gamma

• unlike wild-type, mutant peritoneal macrophages fail to secrete TNF in response to increasing concentrations of S. minnesota LPS

• mutant peritoneal macrophages show severely impaired production of TNF, IL-6 and NO₂^- in response to S. aureus lipoteichoic acid

• however, mutant peritoneal macrophages display normal production of NO₂^- in response to S. aureus peptidoglycan plus IFN-gamma

abnormal level of surface class II molecules ( J:76115 )

• unlike wild-type splenocytes, mutant B cells fail to exhibit augmentation of MHC class II expression in response to S. minnesota LPS

• in contrast, augmentation of MHC class II expression in response to IL-4 is normal, indicating that this defect is LPS-specific

decreased interleukin-6 secretion ( J:76115 )

• mutant thioglycollate-elicited peritoneal macrophages fail to produce any detectable levels of IL-6 in response to 1 ng/ml of Salmonella minnesota (Re-595) LPS or synthetic E. coli-type lipid A, even in the presence of IFN-gamma

• mutant peritoneal macrophages show severely impaired production of IL-6 in response to S. aureus lipoteichoic acid

• in contrast, mutant peritoneal macrophages produce comparable amounts of IL-6 in response to S. aureus peptidoglycan

decreased tumor necrosis factor secretion ( J:76115 )

• mutant thioglycollate-elicited peritoneal macrophages fail to produce any detectable levels of TNF in response to 1 ng/ml of Salmonella minnesota (Re-595) LPS or synthetic E. coli-type lipid A, even in the presence of IFN-gamma

• unlike wild-type, mutant peritoneal macrophages fail to secrete TNF in response to various concentrations of S. minnesota LPS

• mutant peritoneal macrophages show a significant reduction in TNF secretion in response to cell wall preparations from S. aureus; however, TNF production in response to C. diphtheria and N. coeliaca cell walls is not severely affected

• mutant, but not wild-type, peritoneal macrophages display a severely impaired production of TNF in response to S. aureus and S. sanguis lipoteichoic acid

• however, mutant peritoneal macrophages show a normal, dose-dependent increase in TNF levels in response to S. aureus peptidoglycan

decreased susceptibility to endotoxin shock ( J:76115 )

• following an i.p. injection with E. coli O55:B5-derived LPS (1.0 mg), all homozygotes remain alive on day 6, whereas most wild-type controls succumb to shock 1-5 days after challenge, with only one-fifth surviving on day 6

increased susceptibility to bacterial infection ( J:111778 )

• when infected i.p. with S. typhimurium, Tlr4 mutants show increased susceptibility (100% mortality by 4 days) compared to wild-type or Tlr5 mutants (100% mortality by 5 days)

• at dose of 6 x 10⁶ cfu, mutants succumb to infection by 2 days, similar to wild-type and Tlr5 mutants

hematopoietic system

decreased B cell proliferation ( J:76115 )

• unlike wild-type splenocytes, mutant B cells fail to exhibit a proliferative response to various concentrations of S. minnesota LPS

abnormal macrophage physiology ( J:76115 )

• in culture, mutant thioglycollate-elicited peritoneal macrophages fail to produce any detectable levels of IL-6 and TNF in response to 1 ng/ml of Salmonella minnesota (Re-595) LPS or synthetic E. coli-type lipid A, even in the presence of IFN-gamma

• mutant thioglycollate-elicited peritoneal macrophages fail to produce any NO₂^- in response to S. minnesota LPS or lipid A, even in the presence of IFN-gamma

• unlike wild-type, mutant peritoneal macrophages fail to secrete TNF in response to increasing concentrations of S. minnesota LPS

• mutant peritoneal macrophages show severely impaired production of TNF, IL-6 and NO₂^- in response to S. aureus lipoteichoic acid

• however, mutant peritoneal macrophages display normal production of NO₂^- in response to S. aureus peptidoglycan plus IFN-gamma

homeostasis/metabolism

decreased incidence of tumors by chemical induction ( J:162097 )

• skin cancers induced using croton oil and 7,12-dimethylbenz(a)anthracene

• reduced number of papillomas and carcinomas relative to controls

• growth of established tumors not affected in tumor transplant studies

neoplasm

decreased incidence of tumors by chemical induction ( J:162097 )

• skin cancers induced using croton oil and 7,12-dimethylbenz(a)anthracene

• reduced number of papillomas and carcinomas relative to controls

• growth of established tumors not affected in tumor transplant studies

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

cellular

decreased B cell proliferation ( J:76115 )

• unlike wild-type splenocytes, mutant B cells fail to exhibit a proliferative response to various concentrations of S. minnesota LPS

Genotype
MGI:3588776

hm5

• Allelic Composition: Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J

immune system

impaired neutrophil chemotaxis ( J:98224 )

• decreased neutrophil chemotaxis

enlarged mesenteric lymph nodes ( J:98224 )

• weights of mesenteric lymph nodes 2X controls

abnormal acute inflammation ( J:98224 )

• colitis induced by dextran sodium sulfate involves less inflammatory cell infiltration with fewer neurophils in the lamina propria and submucosa

• epithelial damage normal but decreased epithelial proliferation

• earlier and more severe rectal bleeding

increased susceptibility to bacterial infection ( J:98224 )

• increased numbers of gram (-) bacteria in mesenteric lymph node

hematopoietic system

impaired neutrophil chemotaxis ( J:98224 )

• decreased neutrophil chemotaxis

decreased hemoglobin content ( J:98224 )

• reduced hemoglobin in mice with colitis induced by dextran sodium sulfate

cellular

impaired neutrophil chemotaxis ( J:98224 )

• decreased neutrophil chemotaxis

Genotype
MGI:3629223

ht6

• Allelic Composition: Tlr4^tm1Aki/Tlr4^lps-2J
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * DBA/2J

immune system

abnormal inflammatory response ( J:107391 )

• in response to inhaled LPS, mice respond indistinguishably from Tlr4-deficient mice (no response)

Genotype
MGI:3771394

cn7

• Allelic Composition: Stat3^tm2Aki/Stat3^tm2Aki; Tlr4^tm1Aki/Tlr4^tm1Aki; Lyz2^tm1(cre)Ifo/Lyz2⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

immune system

colitis ( J:83280 )

• few mice exhibit inflammation characteristic of colitis and symptoms were less severe than in Stat3 null mice

decreased interferon-gamma secretion ( J:83280 )

• interferon-gamma production is less than in Stat 3 null mice

decreased susceptibility to endotoxin shock ( J:83280 )

• unlike in wild-type mice, LPS fails to induce cytokine production

digestive/alimentary system

colitis ( J:83280 )

• few mice exhibit inflammation characteristic of colitis and symptoms were less severe than in Stat3 null mice

Genotype
MGI:3625114

cx8

• Allelic Composition: Tlr2^tm1Aki/Tlr2^tm1Aki; Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: B6.129P2-Tlr2^tm1Aki Tlr4^tm1Aki

cellular

increased apoptosis ( J:102879 )

• 5 days after lung injury, mutants show significantly increased numbers of apoptotic lung epithelial and inflammatory cells

homeostasis/metabolism

hyperoxia ( J:102879 )

• mutant mice are more sensitive to hyperoxia; survival time of mutants after hyperoxia exposure is reduced by almost 50% compared to wild-type

increased physiological sensitivity to xenobiotic ( J:102879 )

• double knockout mice are more susceptible to bleomycin-induced lung injury

immune system

abnormal chemokine secretion ( J:102879 )

• hyaluronan fragment-induced expression of chemokines by peritoneal macrophages is completely abolished in double knockout mice

• 5 days after lung injury, mutant mice produce significantly lower amounts of chemotactic factor KC in the alveolar space

respiratory system

abnormal lung interstitium morphology ( J:102879 )

• lung tissue from mutant mice shows evidence of enhanced injury with thickened interstitium and increased inflammatory cell accumulation within the interstitium

Genotype
MGI:3706993

cx9

• Allelic Composition: Tlr2^tm1Kir/Tlr2^tm1Kir; Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: B6.129-Tlr2^tm1Kir Tlr4^tm1Aki

mortality/aging

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

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

• mice are resistant to lethal toxemia induced by heat-inactivated E. coli, whereas wild-type mice die

Genotype
MGI:3665470

cx10

• Allelic Composition: Tlr4^tm1Aki/Tlr4^tm1Aki; Tlr5^tm1Flv/Tlr5^tm1Flv
• Genetic Background: involves: 129P2/OlaHsd * 129S1/Sv * C57BL/6

immune system

increased susceptibility to bacterial infection ( J:111778 )

• double mutants are somewhat more susceptible to infection than either single mutant (100% mortality by 2.5 days)

• upon infection i.n. with P. aeruginosa (1 x 10⁶ cfu), double mutants show increased susceptibility (decreased survival to ~65%)

• at dose of 6 x 10⁶ cfu, mutants succumb to infection by 12 hours

Genotype
MGI:3706954

cx11

• Allelic Composition: Npc1^m1N/Npc1^m1N; Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd * BALB/c

immune system

abnormal cytokine secretion ( J:118352 )

• fibroblasts isolated from 6-week old double null mice secrete ~30% of levels in Tlr-4-sufficient, Npc1-null fibroblasts

nervous system

nervous system phenotype ( J:118352 )

N • number of activated glial cells in brains of double mutants is not different from Npc1-null brains

Genotype
MGI:3588777

cx12

• Allelic Composition: Apoe^tm1Unc/Apoe^tm1Unc; Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

cardiovascular system

abnormal susceptibility to atherosclerosis ( J:91481 )

• 24% reduction in atherosclerotic lesions relative to mice homozygous only for Apoe^tm1Unc

• reduced lipid content of aortic sinus plaques

• reduced infiltration of plaques by macrophage

Genotype
MGI:3707238

cx13

• Allelic Composition: Tlr2^tm1Aki/Tlr2^tm1Aki; Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

immune system

decreased IgG3 level ( J:117688 )

• significantly reduced in serum at 7 and 11 weeks of age

abnormal macrophage physiology ( J:117688 )

• in response to purified LPS, a Tlr4 agonist, or a Tlr2 agonist, macrophages do not produced TNFalpha or Il10, while production after stimulation by CpG, a Tlr9 agonist

• production of these cytokines is reduced upon stimulation with heat-killed gram negative bacteria, whereas response to gram-positive bacteria is comparable to wild-type

abnormal cytokine secretion ( J:117688 )

• TNFalpha and Il10 production is absent in response to Tlr2 or Tlr4 agonists, and is reduced in response to heat-killed gram negative bacteria

hematopoietic system

decreased IgG3 level ( J:117688 )

• significantly reduced in serum at 7 and 11 weeks of age

abnormal macrophage physiology ( J:117688 )

• in response to purified LPS, a Tlr4 agonist, or a Tlr2 agonist, macrophages do not produced TNFalpha or Il10, while production after stimulation by CpG, a Tlr9 agonist

• production of these cytokines is reduced upon stimulation with heat-killed gram negative bacteria, whereas response to gram-positive bacteria is comparable to wild-type