Deficiency of PKCλ/ι alleviates the liver pathologic impairment of Schistosoma japonicum infection by thwarting Th2 response

Abstract

Background The activation of immune response driven by the eggs of Schistosoma japonicum and the subsequent secretions is the culprit behind granulomatous inflammation and liver fibrosis. Evidence suggests that PKCλ/ι participates in a variety of physiological and pathological processes, including the regulation of metabolism, growth, proliferation and differentiation of cells. However, the role of PKCλ/ι in liver disease caused by Schistosoma japonicum remains unclear. Methods In the present study, we observe the pathological changes of egg-induced granulomatous inflammation and fibrosis in the liver of mice infected by Schistosoma japonicum by using conditional PKCλ/ι-knockout mice and wild-type control. Immune cytokines and fibrogenic factors were analyzed by performing flow cytometry and real-time fluorescence quantitative PCR. Results The results of H&E and Masson staining show that the degree of granulomatous lesions and fibrosis in the liver of the infected PKCλ/ι-knockout mice was significantly reduced compared with those of the infected wild-type mice. The mean area of single granuloma and hepatic fibrosis in the PKCλ/ι-knockout mice was significantly lower than that of the wild-type mice (85,295.10 ± 5399.30 μm2 vs. 1,433,702.04 ± 16,294.01 μm2, P < 0.001; 93,778.20 ± 8949.05 μm2 vs. 163,103.01 ± 11,103.20 μm2, P < 0.001), respectively. Serological analysis showed that the ALT content was significantly reduced in the infected knockout mice compared with infected wild-type mice. RT-PCR analysis showed that IL-4 content in knockout mice was significantly increased after Schistosoma japonicum infection, yet the increase was less than that in infected wild-type mice (P < 0.05). PKCλ/ι deficiency led to reduced expression of fibrosis-related factors, including TGF-β1, Col-1, Col-3, α-SMA and liver DAMP factor HMGB1. Flow cytometry analysis showed that the increasing percentage of Th2 cells, which mainly secrete IL-4 cytokines in spleen cells, was significantly lower in PKCλ/ι-deficient mice compared with wild-type mice after infection (P < 0.05). Conclusions Our data demonstrate that PKCλ/ι deficiency alleviating granulomatous inflammation and fibrosis in the liver of mice with S. japonicum infection by downregulating Th2 immune response is the potential molecular mechanism behind the role of PKCλ/ι in schistosomiasis. Graphical Abstract

B cell depletion with anti-CD20 promotes neuroprotection in a BAFF-dependent manner in mice and humans

“…However, we did not observe any alteration in T cell cytokine production in the leptomeninges in dual-treated anti-CD20/anti-BAFF mice compared to that in anti-CD20 treatment alone, suggesting that anti-BAFF treatment did not elevate inflammation. Moreover, the anti-BAFF antibody that we used (Sandy-2) has not been reported to cause tissue pathology in models of hepatic fibrosis (72), chronic colitis (73), or aortic aneurysm (74). Moreover, our orthogonal findings in humans (Fig.…”

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

“…After 4 weeks of Schistosoma japonicum infection, along with the production of schistosome eggs, the host’s immune response transforms into a T-helper 2 ( Th2 ) type immune response, which is marked by increased secretion of Th2 type cytokines, such as IL4, IL-5, and IL-13 ( Stadecker et al., 2004 ). Th2-type cytokines promote the polarization of macrophages to M2-type macrophages, while M2-type macrophages and Th2 maintain a high level of type II immune response in their microenvironment ( Mei et al., 2022 ). Type II cytokines inhibit excessive activation of the inflammatory response and promote the formation of egg granulomas ( Chen et al., 2014 ).…”