MyD88-deficiency increases the risk of diabetic mellitus.

<p>Both genotypes were fed a NCD until 6 weeks of age and then fed a NCD or HFD for 10 weeks. Mice were fasted for 16 h (from 18:00 to 10:00) and subjected to a glucose tolerance test (GTT). We measured circulating levels of glucose at the time indicated (0.5-4 h). (<b>A</b>) NCD-fed mice. (<b>B</b>) HFD-fed mice. (<b>C</b>) NCD- and HFD-fed mice, which were fasted for 16 h. (<b>D</b>) Glucose levels after GTT (2 h time point) of each genotype of mice fed the NCD or HFD. n = 6∼12/group. *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001 v.s. control mice.</p

Increased circulating levels of insulin and leptin in MyD88-deficient mice.

<p>(<b>A</b>) Plasma insulin was measured in each genotype fed the NCD (n = 9–10) or HFD (n = 10–15) at the age of 16 weeks. *<i>p</i><0.05 (<b>B</b>) Plasma leptin was measured in each genotype fed the NCD (n = 9–16) or HFD (n = 11–12) at the age of 16 weeks. **<i>p</i><0.01, ***<i>p</i><0.001.</p

MyD88-deficiency did not affect body weight, adiposity, food intake or locomotor activities.

<p>(<b>A</b>) Body weight gain was measured in control and MyD88-deficient mice. Both genotypes were fed a NCD until 6 weeks of age and then fed a NCD or HFD for 10 weeks. NCD (n = 21–29) and HFD (n = 20–26)-fed mice were examined at the age of 16 weeks. (<b>B</b>) Control and MyD88-deficient mice were fed the HFD from the age of 6 weeks and body weight gain was measured every week (10 weeks). (n = 16–23) (<b>C</b>) Visceral fat was measured at the age of 18 weeks. NCD (n = 8) HFD (n = 6–8) (<b>D</b>) Typical photograph of each genotype of mice fed the NCD or HFD. (<b>EF</b>) Fifteen hours (From19:00 to 10:00) of food intake was measured in each genotype of mice fed the NCD or HFD at the age of 16 weeks. n = 11–13/group (<b>G</b>) Locomotor activities (5 min) were measured in each genotype of mice fed the NCD or HFD at the age of 16 weeks. n = 11–14/group.</p

JNK activation without affecting TNF-α levels in MyD88-deficient mice fed the HFD.

<p>(<b>A</b>) Western blot analysis of p-JNK in liver samples at the age of 18 weeks. Each genotype of mice was fed the NCD (n = 7) or HFD (n = 6–8). ***<i>p</i><0.001 (<b>B</b>) mRNA level of TNF-α was measured in liver samples at the age of 18 weeks. (n = 6–8) **<i>p</i><0.01.</p

MyD88-deficient mice fed the HFD developed liver dysfunction.

<p>(<b>A</b>) Western blot analysis of cleaved PARP in liver samples at the age of 18 weeks. Each genotype of mice was fed the NCD (n = 7) or HFD (n = 6–8). **<i>p</i><0.01 (<b>B</b>) Serum ALT levels were measured at the age of 18 weeks. Each genotype of mice was fed the NCD (n = 8) or HFD (n = 6–7). **<i>p</i><0.01.</p

Aggregation was not formed in p62 and APP-ΔCT co-transfectant cells

 Western blot revealed that aggregation was not formed p62 and APP-⊿CT co-transfectant in N2a neurons.  </p

Image_3_Basophils activation of patients with chronic spontaneous urticaria in response to C5a despite failure to respond to IgE-mediated stimuli.tif

Urticaria is characterized by the occurrence of wheals and flares in response to vasoactive mediators, such as histamine. Various studies have suggested the involvement of basophils in the pathogenesis of chronic spontaneous urticaria (CSU). However, histamine release from peripheral basophils in response to stimuli acting on the high affinity IgE receptor (FcϵRI) is impaired in many patients with CSU (non/low responders). We previously demonstrated that tissue factor (TF)s expressed on vascular endothelial cells in response to a combination of various stimuli, such as that of histamine and lipopolysaccharide (LPS), activates the extrinsic coagulation pathway and produces anaphylatoxin, complement 5a (C5a), which then activates basophils and mast cells via the C5a receptor (C5aR). We have revealed that histamine release was induced in response to C5a and formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), regardless of the response to anti-IgE antibody, the reduced numbers of basophils and severity of urticaria. Moreover, we found that spontaneous release of histamine ex vivo from basophils of patients with CSU is higher than that from healthy individuals. These results suggest that basophils and the complement system, which could be activated by coagulation factors, may play a critical role in the pathogenesis of CSU, especially in cases refractory to treatment involving the IgE/FcϵRI pathway.</p

Image_4_Basophils activation of patients with chronic spontaneous urticaria in response to C5a despite failure to respond to IgE-mediated stimuli.tif

Urticaria is characterized by the occurrence of wheals and flares in response to vasoactive mediators, such as histamine. Various studies have suggested the involvement of basophils in the pathogenesis of chronic spontaneous urticaria (CSU). However, histamine release from peripheral basophils in response to stimuli acting on the high affinity IgE receptor (FcϵRI) is impaired in many patients with CSU (non/low responders). We previously demonstrated that tissue factor (TF)s expressed on vascular endothelial cells in response to a combination of various stimuli, such as that of histamine and lipopolysaccharide (LPS), activates the extrinsic coagulation pathway and produces anaphylatoxin, complement 5a (C5a), which then activates basophils and mast cells via the C5a receptor (C5aR). We have revealed that histamine release was induced in response to C5a and formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), regardless of the response to anti-IgE antibody, the reduced numbers of basophils and severity of urticaria. Moreover, we found that spontaneous release of histamine ex vivo from basophils of patients with CSU is higher than that from healthy individuals. These results suggest that basophils and the complement system, which could be activated by coagulation factors, may play a critical role in the pathogenesis of CSU, especially in cases refractory to treatment involving the IgE/FcϵRI pathway.</p

Image_1_Basophils activation of patients with chronic spontaneous urticaria in response to C5a despite failure to respond to IgE-mediated stimuli.tif

Urticaria is characterized by the occurrence of wheals and flares in response to vasoactive mediators, such as histamine. Various studies have suggested the involvement of basophils in the pathogenesis of chronic spontaneous urticaria (CSU). However, histamine release from peripheral basophils in response to stimuli acting on the high affinity IgE receptor (FcϵRI) is impaired in many patients with CSU (non/low responders). We previously demonstrated that tissue factor (TF)s expressed on vascular endothelial cells in response to a combination of various stimuli, such as that of histamine and lipopolysaccharide (LPS), activates the extrinsic coagulation pathway and produces anaphylatoxin, complement 5a (C5a), which then activates basophils and mast cells via the C5a receptor (C5aR). We have revealed that histamine release was induced in response to C5a and formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), regardless of the response to anti-IgE antibody, the reduced numbers of basophils and severity of urticaria. Moreover, we found that spontaneous release of histamine ex vivo from basophils of patients with CSU is higher than that from healthy individuals. These results suggest that basophils and the complement system, which could be activated by coagulation factors, may play a critical role in the pathogenesis of CSU, especially in cases refractory to treatment involving the IgE/FcϵRI pathway.</p

Image_2_Basophils activation of patients with chronic spontaneous urticaria in response to C5a despite failure to respond to IgE-mediated stimuli.tif

Urticaria is characterized by the occurrence of wheals and flares in response to vasoactive mediators, such as histamine. Various studies have suggested the involvement of basophils in the pathogenesis of chronic spontaneous urticaria (CSU). However, histamine release from peripheral basophils in response to stimuli acting on the high affinity IgE receptor (FcϵRI) is impaired in many patients with CSU (non/low responders). We previously demonstrated that tissue factor (TF)s expressed on vascular endothelial cells in response to a combination of various stimuli, such as that of histamine and lipopolysaccharide (LPS), activates the extrinsic coagulation pathway and produces anaphylatoxin, complement 5a (C5a), which then activates basophils and mast cells via the C5a receptor (C5aR). We have revealed that histamine release was induced in response to C5a and formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), regardless of the response to anti-IgE antibody, the reduced numbers of basophils and severity of urticaria. Moreover, we found that spontaneous release of histamine ex vivo from basophils of patients with CSU is higher than that from healthy individuals. These results suggest that basophils and the complement system, which could be activated by coagulation factors, may play a critical role in the pathogenesis of CSU, especially in cases refractory to treatment involving the IgE/FcϵRI pathway.</p