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

Abstract

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.

A Pathogenic Role for FcγRI in the Immune Response against Chlamydial Respiratory Infection

“…To determine the participation of FcγRI in chlamydial infection, we employed our established model of chlamydial respiratory infection by intranasal injection of C. muridarum into C57 BL/6 mice as previously described [ 10 , 16 ]. As the 3 days post-infection (3 d p.i.…”

“…Next, we investigated the cellular sources of FcγRI to identify its action targets during the chlamydial defense. According to reports, mFcγRI expression appears to be restricted on the surface of myeloid cells including monocytes, macrophages, moDCs, and activated neutrophils [ 9 , 10 , 11 ]. To clarify the expression pattern of FcγRI on individual immune cell compartments following chlamydial infection, a multicolor flow cytometry strategy was employed ( Supplementary Figure S1 ).…”

“…These single-cell suspensions were prepared as described previously [ 10 , 17 ]. Briefly, sterile-isolated lung tissue from mice at different time points post infection was minced and incubated with collagenase XI (Sigma-Aldrich, Ronkonkoma, N.Y., USA) at 37 °C for 55 min.…”

“…Fcγ-receptors (FcγRs) are receptors specific to the IgG Fc portion and can be functionally divided into activating (FcγRI, FcγRIII, and FcγRIV) and inhibitory (FcγRIIB) receptors, which transmit signals via immunoreceptor tyrosine-based activation (ITAM) or inhibitory motifs (ITIM) [ 8 ]. Among them, FcγRI is the only activating receptor that binds IgG2a with high affinity and has shown to be constitutively expressed on the surface of monocytes, macrophages, and monocyte-derived dendritic cells (moDCs), as well as inducible on neutrophils under inflammatory conditions [ 9 , 10 , 11 ]. In recent years, many in vivo observations in FcγRI-deficient mice suggest a pleiotropic regulatory role of FcγRI in the immune system, as described in several infections and inflammatory diseases such as Arthus reaction, arthritis, Bordetella pertussis infection, and Porcine reproductive and respiratory syndrome virus (PRRSV) infection [ 12 , 13 , 14 ].…”

IL-21/IL-21R Promotes the Pro-Inflammatory Effects of Macrophages during C. muridarum Respiratory Infection

“…In most cases, an efficient immune response is mounted involving recruitment of innate immune cells and eventual clearance of the infection. As such, professional phagocytes, primarily macrophages and neutrophils, act as gatekeepers to contain and resolve infection [ 7 , 8 ].…”