IL-21/IL-21R was documented to participate in the regulation of multiple infection and inflammation. During Chlamydia muridarum (C. muridarum) respiratory infection, our previous study had revealed that the absence of this signal induced enhanced resistance to infection with higher protective Th1/Th17 immune responses. Here, we use the murine model of C. muridarum respiratory infection and IL-21R deficient mice to further identify a novel role of IL-21/IL-21R in neutrophilic inflammation. Resistant IL-21R-/- mice showed impaired neutrophil recruitment to the site of infection. In the absence of IL-21/IL-21R, pulmonary neutrophils also exhibited reduced activation status, including lower CD64 expression, MPO activity, and neutrophil-produced protein production. These results correlated well with the decrease of neutrophil-related chemokines (KC and MIP-2), inflammatory cytokines (IL-6, IL-1β, and TNF-α), and TLR/MyD88 pathway mediators (TLR2, TLR4, and MyD88) in infected lungs of IL-21R-/- mice than normal mice. Complementarily, decreased pulmonary neutrophil infiltration, activity, and levels of neutrophilic chemotactic factors and TLR/MyD88 signal in infected lungs can be corrected by rIL-21 administration. These results revealed that IL-21/IL-21R may aggravate the neutrophil inflammation through regulating TLR/MyD88 signal pathway during chlamydial respiratory infection.

FcγRI is an important cell surface receptor reported to be involved in multiple immune responses, although it has not yet been extensively studied in intracellular bacterial infections. Here, using a mouse model of C. muridarum respiratory infection, we were able to determine how FcγRI regulates the host resistance against chlamydial invasion. According to our findings, the chlamydial loads and pulmonary pathology were both reduced in FcγRI deficient (Fcgr1−/−) animals. Being infected, monocytes, macrophages, neutrophils, DCs, CD4+/CD8+ T cells, and effector Th1 subsets displayed increased FcγRI expression patterns. Altered infiltration of these cells in the lungs of Fcgr1−/− mice further demonstrated the regulation of FcγRI in the immune system and identified Th1 cells and macrophages as its target cell populations. As expected, we observed that the Th1 response was augmented in Fcgr1−/− mice, while the pro-inflammatory M1 macrophage polarization was constrained. These findings might indicate FcγRI as a potential regulator for host immunity and inflammatory response during chlamydial infection.

Chlamydia trachomatis usually causes mucosal infections, bringing considerable morbidity and socioeconomic burden worldwide. We previously revealed that IL-27/IL-27R mediates protection against chlamydial invasion by promoting a protective Th1 response and suppressing neutrophilic inflammation. Here, we used the mouse model of Chlamydia muridarum (C. muridarum) respiratory infections to further investigate the impact of IL-27 signaling in the DCs-regulated immune response, since an elevated IL-27/IL-27R expression in DCs was identified following chlamydial infection. An adoptive transfer of Chlamydia muridarum-stimulated DCs to wild-type mice approach was subsequently used, and the donor-DCs-promoted resistance with a higher Th1 response against chlamydial infection was attenuated when DCs lacking IL-27R were used as donor cells. Flow cytometry analysis revealed the suppression of IL-27 signaling on DCs phenotypic maturation. A further functional maturation analysis of DCs revealed that IL-27 signaling restricted the protein and mRNA expression of IL-10 from DCs following infection. Thus, these findings suggest that IL-27 signaling could support the Th1 response via inhibiting IL-10 production in DCs, thus mediating the protective host defense against chlamydial respiratory infection.

Countries around the world have become concerned about their responsibility to protect the environment and resources. In this paper, we established a model of multi-period PSW-DID (weighted propensity score matching- differences-in-differences) to test the effect of China’s audit of natural resource. We found that: (1) local governments had a strategic incentive to reduce pollution, they paid more attention to environmental performance linked to individual promotion than to green innovation and development. (2) Compared with the long-term and complexity of water pollution control, they paid more attention to air pollution treatment. (3) In the long run, the environmental audit was indeed beneficial to the improvement of environmental quality, but the time of taking effect was the second year (one-year lag). (4) In addition, because of the contradiction between the neglect of human capital and the timeliness of environmental supervision, the local government did not show substantial pollution reduction. Therefore, local officials should foster the long-term responsibility consciousness of green innovation and pay more attention to the integration of human capital. The audit of natural resources should establish a long-term mechanism, which could establish a complete accountability system or change off-office audit to interim audit. The construction of audit big data platforms should pay more attention to substantive characteristic data, such as data on population inflow, which is not only a paper score of air pollution. This study can reveal the dilemma of pollution prevention and control in China, urge local governments to promote the rational flow of human resources, improve the innovation level, and achieve substantive pollution control and efficiency enhancement of green development.

Interleukin-21 and its receptors (IL-21/IL-21R) aggravate chlamydial lung infection, while macrophages (Mφ) are one of the main cells infected by chlamydia and the main source of inflammatory cytokines. Therefore, it is particularly important to study whether IL-21/IL-21R aggravates chlamydia respiratory infection by regulating Mφ. Combined with bioinformatics analysis, we established an IL-21R-deficient (IL-21R−/−) mouse model of Chlamydia muridarum (C. muridarum) respiratory tract infection in vivo, studied C. muridarum-stimulated RAW264.7 by the addition of rmIL-21 in vitro, and conducted adoptive transfer experiments to clarify the association between IL-21/IL-21R and Mφ. IL-21R−/− mice showed lower infiltration of pulmonary total Mφ, alveolar macrophages, and interstitial macrophages compared with WT mice following infection. Transcriptomic analysis suggested that M1-related genes are downregulated in IL-21R−/− mice and that IL-21R deficiency affects the Mφ-mediated inflammatory response during C. muridarum infection. In vivo experiments verified that in IL-21R−/− mice, pulmonary M1-type CD80+, CD86+, MHC II+, TNFα+, and iNOS+ Mφ decreased, while there were no differences in M2-type CD206+, TGF-β+, IL-10+ and ARG1+ Mφ. In vitro, administration of rmIL-21 to C. muridarum-stimulated RAW264.7 cells promoted the levels of iNOS-NO and the expression of IL-12p40 and TNFα, but had no effect on TGFβ or IL-10. Further, adoptive transfer of M1-like bone marrow-derived macrophages derived from IL-21R−/− mice, unlike those from WT mice, effectively protected the recipients against C. muridarum infection and induced relieved pulmonary pathology. These findings help in understanding the mechanism by which IL-21/IL-21R exacerbates chlamydia respiratory infection by promoting the proinflammatory effect of Mφ.