IL-4/IL-13–mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury

Abstract

Cytokines IL-4 and IL-13 play important roles in polarization of macrophages/dendritic cells to an M2 phenotype, which is important for recovery from acute kidney injury. Both IL-4 and IL-13 activate JAK3/STAT6 signaling. In mice with diphtheria toxin receptor expression in proximal tubules (selective injury model), a relatively selective JAK3 inhibitor, tofacitinib, led to more severe kidney injury, delayed recovery from acute kidney injury, increased inflammatory M1 phenotype markers and decreased reparative M2 phenotype markers of macrophages/dendritic cells, and development of more severe renal fibrosis after diphtheria toxin administration. Similarly, there was delayed recovery and increased tubulointerstitial fibrosis in these diphtheria toxin-treated mice following tamoxifen-induced deletion of both IL-4 and IL-13, with increased levels of M1 and decreased levels of M2 markers in the macrophages/dendritic cells. Furthermore, deletion of IL-4 and IL-13 led to a decrease of tissue reparative M2a phenotype markers but had no effect on anti-inflammatory M2c phenotype markers. Deletion of IL-4 and IL-13 also inhibited recovery from ischemia-reperfusion injury in association with increased M1 and decreased M2 markers and promoted subsequent tubulointerstitial fibrosis. Thus, IL-4 and IL-13 are required to effectively polarize macrophages/dendritic cells to an M2a phenotype and to promote recovery from acute kidney injury.

Renal regeneration after acute kidney injury

“…When pro‐inflammatory M1 macrophages acquire a tissue healing phenotype, they are called M2 or alternatively activated. Recently, IL‐4 and IL‐13 cytokines were demonstrated to be required to polarize DCs and macrophages to a M2 phenotype in a mice model, which was associated with recovery from renal injury . Indeed, animal models show that M2 macrophages predominate in the repair phase of AKI .…”

“…74 Recently, IL-4 and IL-13 cytokines were demonstrated to be required to polarize DCs and macrophages to a M2 phenotype in a mice model, which was associated with recovery from renal injury. 75 Indeed, animal models show that M2 macrophages predominate in the repair phase of AKI. 76 Unlike its classically activated counterpart, M2 macrophages do not present antigens to T cells nor produce significant amounts of inflammatory cytokines or toxic factors.…”

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“…Conversely, IL-4/IL-13-expressing CD4 + T cells play important roles in polarization of macrophages/dendritic cells to the M2a phenotype, important for recovery from acute kidney injury through activation of Janus kinase 3/ signal transducer and activator of transcription 6 (JAK3/ STAT-6) signaling [31,32]. M2a macrophages are considered beneficial in reparative processes with respect to ongoing injury; however, sustained activity may result in the continuous production of various wound-healing growth factors, ultimately becoming a pathological process leading to fibrosis [20,[32][33][34]. Steroids and CNI also induce M2a polarization, promoting development of fibrosis and at times exacerbating rejection [33].…”

Infectious agents as potential triggers for autoimmunity in achalasia

“…IL-13 has also associated with increased esophageal body contractility in achalasia 49 . On the other hand, IL-4/IL-13− expressing CD4+ T cells play important roles in polarization of macrophages/dendritic cells to the M2a phenotype 50,51 . M2a macrophages are considered beneficial in reparative processes with respect to ongoing injury; however, sustained activity may result in the continuous production of various wound healing growth factors, ultimately becoming a pathological process leading to fibrosis (Fig.…”

“…M2a macrophages are considered beneficial in reparative processes with respect to ongoing injury; however, sustained activity may result in the continuous production of various wound healing growth factors, ultimately becoming a pathological process leading to fibrosis (Fig. 2) [50][51][52][53][54][55] . Its expression pattern in patients with achalasia is also like that of IL-4 12 .…”