Macrophages play diverse roles in development, homeostasis, and immunity. Accordingly, the dysfunction of macrophages is involved in the occurrence and progression of various diseases, such as coronavirus disease 2019 and atherosclerosis. The protective or pathogenic effect that macrophages exert in different conditions largely depends on their functional plasticity, which is regulated via signal transduction such as Janus kinase–signal transducer and activator of transcription, Wnt and Notch pathways, stimulated by environmental cues. Over the past few decades, the molecular mechanisms of signaling pathways in macrophages have been gradually elucidated, providing more alternative therapeutic targets for diseases treatment. Here, we provide an overview of the basic physiology of macrophages and expound the regulatory pathways within them. We also address the crucial role macrophages play in the pathogenesis of diseases, including autoimmune, neurodegenerative, metabolic, infectious diseases, and cancer, with a focus on advances in macrophage‐targeted strategies exploring modulation of components and regulators of signaling pathways. Last, we discuss the challenges and possible solutions of macrophage‐targeted therapy in clinical applications. We hope that this comprehensive review will provide directions for further research on therapeutic strategies targeting macrophage signaling pathways, which are promising to improve the efficacy of disease treatment.

Background: Domestic violence does not only violate women’s fundamental human rights but it also undermines them from achieving their fullest potential around the world. This study was conducted to assess trends and factors associated with domestic violence among married women of reproductive age in Zimbabwe. Method: This was a cross-sectional study which used secondary data obtained from 2005/06, 2010/11 and 2015 Zimbabwe Demographic and Health Surveys (ZDHS). Respondents ranged from married or living with a partner (15–49 years). Multiple logistic regression analysis was used to examine factors associated with domestic violence. Results: Out of 4472 women who were currently married, 1907 (42.7%) had ever experienced one form of domestic violence (physical, emotional and sexual violence). Women aged 40–49 was deemed a protective factor against domestic violence. Risk of domestic violence was higher among working women than unemployed women [AOR = 1.35; p ≤ 0.047]. Women who drink alcohol significantly risk experiencing domestic violence compared to their non-drinking counterpart; also women whose husbands drink alcohol were at higher risk of experiencing domestic violence [AOR = 1.35; p ≤ 0.001]. Domestic violence was higher among women whose husbands have ever experienced their fathers beating their mothers and significant for women whose husbands have more than one wife (polygamy) [AOR = 1.35; p ≤ 0.001]. High parity (5 or more children) was also a risk factor for domestic violence among the studied population [AOR = 1.35; p ≤ 0.038]. Conclusion: Domestic violence was found to be strongly associated with women whose husbands drink alcohol, products of abusive parents/father beating their mother and/or polygamous marriage (had more than one wife). Domestic violence still remains a challenge and a more biting policy efforts are needed to eradicate this public health canker in Zimbabwe.

Infections of the reproductive tract are known to contribute to testicular inflammatory impairment, leading to an increase of pro-inflammatory cytokines such as IL-1β, and a decline in sperm quality. Prokineticin 2 (PK2), a secretory protein, is closely associated with the secretion of pro-inflammatory cytokines in inflamed tissue. It was reported that increased PK2 is related to the upregulation of IL-1β, but the underlying mechanism remains elusive. Here, we illustrated that PK2 was upregulated in testicular macrophages (TM) in a rat model of uropathogenic Escherichia coli (UPEC) infection, which induced the activation of the NLRP3 inflammasome pathway to boost IL-1β secretion. Administration of PK2 inhibitor alleviated the inflammatory damage and suppressed IL-1β secretion. Moreover, PK2 promoted NLRP3 expression and the release of cleaved IL-1β from TM to the supernatants after the challenge with UPEC in vitro. IL-1β in the supernatants affected Leydig cells by suppressing the expression of genes encoding for the enzymes P450scc and P450c17, which are involved in testosterone production. Overall, we revealed that increased PK2 levels in TM in UPEC-induced orchitis may impair testosterone synthesis via the activation of the NLRP3 pathway. Our study provides a new insight into the mechanisms underlying inflammation-associated male infertility and suggests an anti-inflammatory therapeutic target for male infertility.

Reproductive tract infections contribute to the development of testicular inflammatory lesions, leading to male infertility. Previous research shows that the activation of the NLRP3 inflammasome in orchitis promotes the secretion and maturation of IL-1β and thus decreases male fertility. The calcium-sensing receptor (CaSR) is a calcium-sensitive receptor and closely related to the secretion of proinflammatory cytokines. Increase in CaSR level promotes the assembly and activation of the NLRP3 inflammasome. However, the role of calcium-sensitive receptors in orchitis is unknown. We first constructed a uropathogenic Escherichia Coli (UPEC) rat orchitis model, then detected the expression of CaSR and NLRP3 inflammatory pathway protein in TM through RT-PCR and WB, calcium levels in testicular macrophages (TM) through flow cytometry, and proinflammatory factor IL-1β through ELISA. In addition, testosterone levels in the serum samples waere detected using liquid chromatography-mass spectrometry (LC-MS). Here, we showed that CaSR upregulation after infection in TM in a rat model of UPEC induces the activation of the NLRP3 inflammasome pathway and thereby enhances IL-1β secretion and reduces testosterone level in the blood. Moreover, CaSR inhibitors can alleviate inflammatory impairment. After UPEC challenge in vitro, CaSR promoted NLRP3 expression and released IL-1β cleaved from TM into the supernatant. Overall, elevated CaSR levels in TM in testes with UPEC-induced orchitis may impair testosterone synthesis through the activation of the NLRP3 pathway and PK2 is an upstream regulatory protein of CaSR. Our research further showed the underlying mechanisms of inflammation-related male infertility and provides anti-inflammatory therapeutic targets for male infertility.

Sperm DNA injury is one of the common causes of male infertility. Folic acid deficiency would increase the methylation level of the important genes, including those involved in DNA double‐strand break (DSB) repair pathway. In the early stages, we analysed the correlation between seminal plasma folic acid concentration and semen parameters in 157 infertility patients and 91 sperm donor volunteers, and found that there was a significant negative correlation between seminal folic acid concentration and sperm DNA Fragmentation Index (DFI; r = −0.495, p < 0.01). Then through reduced representation bisulphite sequencing, global DNA methylation of sperm of patients in the low folic acid group and the high folic acid group was analysed, it was found that the methylation level in Rad54 promoter region increased in the folic acid deficiency group compared with the normal folic acid group. Meanwhile, the results of animal model and spermatocyte line (GC‐2) also found that folic acid deficiency can increase the methylation level in Rad54 promoter region, increased sperm DFI in mice, increased the expression of γ‐H2AX, that is, DNA injury marker protein, and increased sensitivity of GC‐2 to external damage and stimulation. The study indicates that the expression of Rad54 is downregulated by folic acid deficiency via DNA methylation. This may be one of the mechanisms of sperm DNA damage caused by folate deficiency.