Macrophage‐derived insulin‐like growth factor‐1 is a key neurotrophic and nerve‐sensitizing factor in pain associated with endometriosis

Forster, Rachel; Sarginson, Alexandra; Velichkova, Atanaska; Hogg, Chloe; Dorning, Ashley; Horne, Andrew; Saunders, Philippa T. K.; Greaves, Erin

doi:10.1096/fj.201900797r

Cited by 109 publications

(132 citation statements)

References 56 publications

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“…Whilst, a number of leukocytes exhibit altered numbers and function in endometriosis, it is evident that macrophages play an unrivaled role in disease pathogenesis. We and others have demonstrated that macrophages are critical for licensing lesion growth, promoting vascularization and innervation as well as contributing to pain in the disorder (53)(54)(55). Lessons from diverse tissues also place macrophages at the center of disease states such as liver injury (56), multiple sclerosis (57), and cancer (52).…”

Section: The Macrophage: a Complex Cell At The Center Of An Enigmaticmentioning

confidence: 98%

Endometriosis-Associated Macrophages: Origin, Phenotype, and Function

2020

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Endometriosis is a complex, heterogeneous, chronic inflammatory condition impacting ∼176 million women worldwide. It is associated with chronic pelvic pain, infertility, and fatigue, and has a substantial impact on health-related quality of life. Endometriosis is defined by the growth of endometrial-like tissue outside the uterus, typically on the lining of the pelvic cavity and ovaries (known as "lesions"). Macrophages are complex cells at the center of this enigmatic condition; they are critical for the growth, development, vascularization, and innervation of lesions as well as generation of pain symptoms. In health, tissue-resident macrophages are seeded during early embryonic life are vital for development and homeostasis of tissues. In the adult, under inflammatory challenge, monocytes are recruited from the blood and differentiate into macrophages in tissues where they fulfill functions, such as fighting infection and repairing wounds. The interplay between tissue-resident and recruited macrophages is now at the forefront of macrophage research due to their differential roles in inflammatory disorders. In some cancers, tumor-associated macrophages (TAMs) are comprised of tissue-resident macrophages and recruited inflammatory monocytes that differentiate into macrophages within the tumor. These macrophages of different origins play differential roles in disease progression. Herein, we review the complexities of macrophage dynamics in health and disease and explore the paradigm that under disease-modified conditions, macrophages that normally maintain homeostasis become modified such that they promote disease. We also interrogate the evidence to support the existence of multiple phenotypic populations and origins of macrophages in endometriosis and how this could be exploited for therapy.

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Section: The Macrophage: a Complex Cell At The Center Of An Enigmaticmentioning

confidence: 98%

Endometriosis-Associated Macrophages: Origin, Phenotype, and Function

2020

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“…Furthermore, in a mouse model of endometriosis, depletion of macrophages resulted in lesions that were reduced in size and vascularity (7), suggesting that macrophages are critical for the development of endometriotic lesions. A separate study further showed that the depletion of macrophages in an endometriosis mouse model drastically reduced markers of inflammatory pain and pain sensitivity behaviors (8).…”

Section: Introductionmentioning

confidence: 98%

IL-17A Modulates Peritoneal Macrophage Recruitment and M2 Polarization in Endometriosis

et al. 2020

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Endometriosis is a debilitating gynecological disease characterized by the extrauterine presence of endometrial-like tissues located on the peritoneal membrane and organs of the pelvic cavity. Notably, dysfunctional immune activation in women with endometriosis could also contribute to the development of disease. In particular, alternatively activated (M2) peritoneal macrophages are shown to aid peritoneal lesion development by promoting remodeling of extracellular matrix and neovascularization of lesions. However, the stimuli responsible for polarizing M2 macrophages in endometriosis remain elusive. Interleukin-17A (IL-17A) can induce M2 macrophage polarization in other disease models and IL-17A is elevated in the plasma and endometriotic lesions of women with endometriosis. In this study, we investigated whether IL-17A could induce macrophage recruitment and M2 polarization, while promoting endometriotic lesion growth through enhanced vascularization. By utilizing a co-culture of macrophage-like THP-1 cells with an endometriotic epithelial cell line, our in vitro results suggest that IL-17A indirectly induces M2 markers CCL17 and CD206 by interacting with endometriotic epithelial cells. Further, in a syngeneic mouse model of endometriosis, IL-17A treatment increased macrophages in the peritoneum, which were also M2 in phenotype. However, IL-17A treatment did not augment proliferation or vascularization of the lesion in the study time frame. These findings suggest that IL-17A may be a stimulus inducing the pathogenic polarization of macrophages into the M2 phenotype by first acting on the endometriotic lesion itself.

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“…It is also known that insulin-like growth factor-1 (IGF-1), a polypeptide growth factor highly similar in sequence to insulin, plays an essential role in the maintenances of various neuronal functions in the central and peripheral nervous system [8,9]. Besides, IGF-1 receptor (IGF-1R) activation by IGF-1 released from infiltrating macrophages induces translocation of transient receptor potential (TRP) vanilloid subfamily type 2 (TRPV2) channel to the cell membrane, resulting in noxious heat or mechanical hypersensitivity [10,11].…”

Section: Introductionmentioning

confidence: 99%

Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain

Sugawara

Shinoda

Hayashi

et al. 2019

IJMS

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Insulin-like growth factor-1 (IGF-1) is upregulated in the injured peripheral nerve bundle and controls nociceptive neuronal excitability associated with peripheral nerve injury. Here, we examined the involvement of IGF-1 signaling in orofacial neuropathic pain following infraorbital nerve injury (IONI) in rats. IONI promoted macrophage accumulation in the injured ION, as well as in the ipsilateral trigeminal ganglion (TG), and induced mechanical allodynia of the whisker pad skin together with the enhancement of neuronal activities in the subnucleus caudalis of the spinal trigeminal nucleus and in the upper cervical spinal cord. The levels of IGF-1 released by infiltrating macrophages into the injured ION and the TG were significantly increased. The IONI-induced the number of transient receptor potential vanilloid (TRPV) subfamily type 4 (TRPV4) upregulation in TRPV subfamily type 2 (TRPV2)-positive small-sized, and medium-sized TG neurons were inhibited by peripheral TRPV2 antagonism. Furthermore, the IONI-induced mechanical allodynia was suppressed by TRPV4 antagonism in the whisker pad skin. These results suggest that IGF-1 released by macrophages accumulating in the injured ION binds to TRPV2, which increases TRPV4 expression in TG neurons innervating the whisker pad skin, ultimately resulting in mechanical allodynia of the whisker pad skin.

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Macrophage‐derived insulin‐like growth factor‐1 is a key neurotrophic and nerve‐sensitizing factor in pain associated with endometriosis

Cited by 109 publications

References 56 publications

Endometriosis-Associated Macrophages: Origin, Phenotype, and Function

Endometriosis-Associated Macrophages: Origin, Phenotype, and Function

IL-17A Modulates Peritoneal Macrophage Recruitment and M2 Polarization in Endometriosis

Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain

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