Androgen-Influenced Polarization of Activin A-Producing Macrophages Accompanies Post-pyelonephritic Renal Scarring

Abstract

Ascending bacterial pyelonephritis, a form of urinary tract infection (UTI) that can result in hospitalization, sepsis, and other complications, occurs in ∼250,000 US patients annually; uropathogenic Escherichia coli (UPEC) cause a large majority of these infections. Although UTIs are primarily a disease of women, acute pyelonephritis in males is associated with increased mortality and morbidity, including renal scarring, and end-stage renal disease. Preclinical models of UTI have only recently allowed investigation of sex and sex-hormone effects on pathogenesis. We previously demonstrated that renal scarring after experimental UPEC pyelonephritis is augmented by androgen exposure; testosterone exposure increases both the severity of pyelonephritis and the degree of renal scarring in both male and female mice. Activin A is an important driver of scarring in non-infectious renal injury, as well as a mediator of macrophage polarization. In this work, we investigated how androgen exposure influences immune cell recruitment to the UPEC-infected kidney and how cell-specific activin A production affects post-pyelonephritic scar formation. Compared with vehicle-treated females, androgenized mice exhibited reduced bacterial clearance from the kidney, despite robust myeloid cell recruitment that continued to increase as infection progressed. Infected kidneys from androgenized mice harbored more alternatively activated (M2) macrophages than vehicle-treated mice, reflecting an earlier shift from a pro-inflammatory (M1) phenotype. Androgen exposure also led to a sharp increase in activin A-producing myeloid cells in the infected kidney, as well as decreased levels of follistatin (which normally antagonizes activin action). As a result, infection in androgenized mice featured prolonged polarization of macrophages toward a pro-fibrotic M2a phenotype, accompanied by an increase in M2a-associated cytokines. These data indicate that androgen enhancement of UTI severity and resulting scar formation is related to augmented local activin A production and corresponding promotion of M2a macrophage polarization.

The impact of biological sex on diseases of the urinary tract

“…Instead, these mice fail to limit infection to the kidney parenchyma, exhibiting increased rates of bacterial dissemination and mortality 53 . In the non-refluxing C57BL/6 strain, female mice treated with testosterone also develop persistent kidney infection 52,53,62,63 . These androgenized C57BL/6 females have increased monocyte recruitment, increased M2-polarized macrophages in the kidney from 14 to 28 days post-infection, and increased kidneyassociated M2 macrophage cytokines CXCL1 and CSF-3 from day Fig.…”

“…10 to 21 post-infection 63 . Finally, androgen exposure in female mice induces a burst of epithelial-derived TGFβ1 at 24 h postinfection, which polarizes macrophages toward an alternatively activated, pro-fibrotic phenotype, promoting the development of scars surrounded by pro-fibrotic M2a macrophages 62,64 .…”

INHBA is a Prognostic Biomarker and Correlated With Immune Cell Infiltration in Cervical Cancer

“…According to our research, there was a significant positive correlation between INHBA expression and macrophage infiltration. Additionally, INHBA has been shown to affect macrophage polarization in vitro Hreha et al (2020) . We hypothesized that INHBA may influence the tumor microenvironment by regulating macrophage polarization, which in turn affects tumor cells.…”

Extracellular vesicles in the pathogenesis and treatment of acute lung injury

“…It has also recently been reported that androgen exposure can induce macrophages to adopt pro- or anti-inflammatory phenotypes. For example, dihydroxy testosterone exposure can promote M1 macrophage polarization in vitro, while cypionate testosterone treatment can induce an androgen-dependent increase in M2 macrophage polarization in a female mouse infection model [ 60 ]. Evidence also suggests that androgens can regulate oxytocin levels, which have been proposed to attenuate cytokine storms, lymphocyte deficiency, thrombosis, ALI/ARDS and organ failure, leading to its proposed use as a treatment for COVID-19 pathogenesis [ 61 ].…”