IL-21/IL-21R Signaling Aggravated Respiratory Inflammation Induced by Intracellular Bacteria through Regulation of CD4+ T Cell Subset Responses

Abstract

The IL-21/IL-21R interaction plays an important role in a variety of immune diseases; however, the roles and mechanisms in intracellular bacterial infection are not fully understood. In this study, we explored the effect of IL-21/IL-21R on chlamydial respiratory tract infection using a chlamydial respiratory infection model. The results showed that the mRNA expression of IL-21 and IL-21R was increased in Chlamydia muridarum–infected mice, which suggested that IL-21 and IL-21R were involved in host defense against C. muridarum lung infection. IL-21R−/− mice exhibited less body weight loss, a lower bacterial burden, and milder pathological changes in the lungs than wild-type (WT) mice during C. muridarum lung infection. The absolute number and activity of CD4+ T cells and the strength of Th1/Th17 responses in IL-21R−/− mice were significantly higher than those in WT mice after C. muridarum lung infection, but the Th2 response was weaker. Consistently, IL-21R−/− mice showed higher mRNA expression of Th1 transcription factors (T-bet/STAT4), IL-12p40, a Th17 transcription factor (STAT3), and IL-23. The mRNA expression of Th2 transcription factors (GATA3/STAT6), IL-4, IL-10, and TGF-β in IL-21R−/− mice was significantly lower than that in WT mice. Furthermore, the administration of recombinant mouse IL-21 aggravated chlamydial lung infection in C57BL/6 mice and reduced Th1 and Th17 responses following C. muridarum lung infection. These findings demonstrate that IL-21/IL-21R may aggravate chlamydial lung infection by inhibiting Th1 and Th17 responses.

Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation

“…FCRL5 plays important roles in autoimmunity with anti-phosphatidylserine antibodies produced by FCRL5 + T-Bet + atypical memory B cells [ 107 ]. IL-21 receptor (IL21R) promotes inflammation in myocardial infarction [ 108 ] and respiratory disease [ 109 ]. CEACAM1 is a coronavirus receptor on endothelial cells as we reported [ 54 ] and promotes vascular aging process [ 110 ].…”

IL-21/IL-21R Regulates the Neutrophil-Mediated Pathologic Immune Response during Chlamydial Respiratory Infection

“…Our recent study had identified moderate disease of IL-21R −/− mice in the host response to C. muridarum infection with enhanced Th1 and Th17 responses (Supplemental Figure 1 and 2 ) [ 3 ]. Resistant IL-21R −/− mice also displayed reduced pulmonary inflammatory pathology with less inflammatory cell infiltration, thus Wright-Giemsa staining of lung cells was performed here and less proportion of pulmonary neutrophils were observed in IL-21R −/− mice than WT mice, especially at day 3 p.i.…”

“…Female wild-type mice (WT; C57BL/6) were purchased from the Huafukang Biotechnology (Beijing, China) with the license number of SCXK (Beijing) 2019-0008. IL-21R −/− mice on the same background were obtained with permission as gifts from Dr. Zhinan Yin (Nankai University, China) as previously described [ 3 ]. Six to 8-week old mice were randomly divided into different groups (3-4 mice per group) according to different infection time points, and all the mice studied were repeated at least 3 times.…”

“…The Chlamydiaceae family comprises a group of Gram-negative obligate intracellular pathogens that have a biphasic development cycle including infectious elementary bodies (EBs) and replicative reticulate bodies (RBs) [ 1 – 3 ]. Among the four commonly recognized species of the genus Chlamydia : Chlamydia trachomatis ( C. trachomatis ), Chlamydia psittaci ( C. psittaci ), Chlamydia pneumoniae ( C. pneumoniae ), and Chlamydia pecorum ( C. pecorum ), the species with the greatest impact on human health is documented to be C. trachomatis [ 2 , 4 ].…”

“…Further results identified increased T-bet/STAT4 (Th1 transcription factors) and STAT3 (Th17 transcription factor) levels in lungs of IL-21R −/− mice following C. muridarum infection. These data suggested the regulation of IL-21/IL-21R on CD4 + T cell subset responses [ 3 ]. However, the latent mechanism and effects of IL-21/IL-21R on innate immune response in C. muridarum respiratory infection remain unclear, thus warranting further investigation.…”