Efficacy of niclosamide on the intra‐abdominal inflammatory environment in endometriosis

Abstract

Endometriosis, a common gynecological disease, causes chronic pelvic pain and infertility in women of reproductive age. Due to the limited efficacy of current therapies, a critical need exists to develop new treatments for endometriosis. Inflammatory dysfunction, instigated by abnormal macrophage (MΦ) function, contributes to disease development and progression. However, the fundamental role of the heterogeneous population of peritoneal MΦ and their potential druggable functions is uncertain. Here we report that GATA6-expressing large peritoneal MΦ (LPM) were increased in the peritoneal cavity following lesion induction. This was associated with increased cytokine and chemokine secretion in the peritoneal fluid (PF), as well as MΦ infiltration, vascularization and innervation in endometriosis-like lesions (ELL). Niclosamide, an FDA-approved anti-helminthic drug, was effective in reducing LPM number, but not small peritoneal MΦ (SPM), in the PF. Niclosamide also inhibits aberrant inflammation in the PF, ELL, pelvic organs (uterus and vagina) and dorsal root ganglion (DRG), as well as MΦ infiltration, vascularization and innervation in the ELL. PF from ELL mice stimulated DRG outgrowth in vitro, whereas the PF from niclosamide-treated ELL mice lacked the strong stimulatory nerve growth response. These results suggest LPM induce aberrant inflammation in endometriosis promoting lesion progression and establishment of the inflammatory environment that sensitizes peripheral nociceptors in the lesions and other pelvic organs, leading to increased hyperalgesia. Our findings provide the rationale for targeting LPM and their functions with niclosamide and its efficacy in endometriosis as a new nonhormonal therapy to reduce aberrant inflammation which may ultimately diminish associated pain.

Progesterone Actions and Resistance in Gynecological Disorders

“…Aberrant p-STAT3, co-occurring with HIF1A, presents in the eutopic endometrium in humans and non-human primates with endometriosis [ 111 ]. Although STAT3 directly interacts with the PRA isoform and is required for normal endometrial functions such as decidualization [ 114 ], STAT3 constitutive stimulation is activated by inflammatory factors from tissue residential or peritoneal immune cells in endometriosis [ 112 , 113 , 115 ]. Yoo et al [ 116 ] have reported that PIAS3, which is a negative regulator of STAT3 activity, is decreased in the eutopic endometrium with endometriosis in humans and non-human primates inversely associated with aberrant p-STAT3.…”

Niclosamide targets macrophages to rescue the disrupted peritoneal homeostasis in endometriosis

“…Disruption of the immune homeostasis in the peritoneal cavity drives the disease development of endometriosis, and macrophages play a central role in this process (Capobianco and Rovere Querini, 2013; Hogg et al, 2020; Shi et al, 2021). Peritoneal macrophages infiltrate endometriotic lesions and promote their growth and vascularization by releasing proinflammatory cytokines and growth factors (Bacci et al, 2009; Cheong et al, 2002; Sekiguchi et al, 2019; Shi et al, 2021).…”

“…Disruption of the immune homeostasis in the peritoneal cavity drives the disease development of endometriosis, and macrophages play a central role in this process (Capobianco and Rovere Querini, 2013; Hogg et al, 2020; Shi et al, 2021). Peritoneal macrophages infiltrate endometriotic lesions and promote their growth and vascularization by releasing proinflammatory cytokines and growth factors (Bacci et al, 2009; Cheong et al, 2002; Sekiguchi et al, 2019; Shi et al, 2021). In addition, IGF1 and netrin-1, along with cytokines secreted by macrophages, also promote neurogenesis and innervation at lesion sites, which enhances the pain sensation in patients (Ding et al, 2021; Forster et al, 2019; Greaves et al, 2015; Scholl et al, 2009).…”

“…The proinflammatory cytokines released by macrophages disrupted in endometriosis also affect multiple important activities of reproduction, such as hormonal balances and decidualization, leading to infertility (De Ziegler et al, 2010; Rasheed and Hamid, 2020). Suppressing the release of proinflammatory cytokines and growth factors from macrophages inhibits lesion growth and endometriosis­associated pain in rodent models (Bacci et al, 2009; Forster et al, 2019; Liu et al, 2018; Shi et al, 2021). Therefore, targeting peritoneal macrophages that are critical for maintaining immune homeostasis in the pelvic cavity could be a new direction for drug development in endometriosis therapy.…”

“…Niclosamide is an FDA-approved anthelmintic drug with multiple clinical trials ongoing to repurpose it for the treatment of other diseases including cancer and metabolic diseases (Chen et al, 2018). We previously reported that niclosamide reduced lesion growth, alleviated aberrant inflammation in peritoneal fluids, and decreased the vascularization and innervation in lesions using mouse models of endometriosis (Prather et al, 2016; Shi et al, 2021).…”