Quick Summary : Macrophages and Helminths
Macrophages are intimately involved in the immune response at every stage of helminth infection, adopt specific phenotypes (generally within the Type 2 orbit) and co-ordinate multiple mechanisms to attack parasites and promote expulsion (Coakley et al., 2020).
Macrophage properties are strongly conditioned by their tissue environment, with some populations (such as alveolar and enteric muscularis macrophages) predisposed to tolerance induction, and other primed to respond to both host (alarmins, chemokines and cytokines) and parasite (pathogen-associated molecular patterns) signals. In the case of helminth infections the Type 2 (M2) or alternatively-activated macrophage (AAM) phenotype predominates, downstream of alarmin (IL-25, IL-33) signals and IL-4R engagement, to which macrophages respond with production of key mediators such as Arginase-1.
The profile of macrophage responses depends on the tissue location, and on the life history of each helminth infection that may involve skin, lung, serous cavity, submucosal and luminal environments. The Maizels lab has worked on macrophages in Brugia malayi, Litomosoides sigmodontis and Heligmosomoides polygyrus model systems, and how products from these parasites modulate macrophage function.
Macrophages in the Maizels Lab: filarial nematodes Brugia malayi and Litomosoides sigmodontis
Mice are resistant to infection with larvae of the human filarial nematode, B. malayi. However, adult worms survive if transplanted intraperitoneally into mice. Within the infected peritoneal cavity, we discovered the first example of in vivo differentiation of “Alternatively Activated Macrophages” (now more commonly termed “M2”). These potently block proliferation of T cells while sparing their ability to produce cytokines (Allen et al., 1996 and Loke et al., 2000). B. malayi-induced macrophages express key products now recognised as signature genes of the M2 phenotype: Arginase-1, RELM-α (aka Fizz1) and Ym1 (aka Chi3l1) Nair et al 2005.
While resistant to B. malayi, mice can harbour a full infection with L. sigmodontis, that establishes in the pleural cavity and is enabled by regulatory T cells (Taylor et al 2005). Early in infection, prior to release of blood-borne microfilariae (MF), suppressive AAMs are found in the pleural cavity; but following appearance of MF, AAM suppression of T cell proliferation becomes systemic (Taylor et al., 2006). Notably AAM effects can be inhibited with anti-TGFβ antibody, further evidence of the role of that cytokine in helminth infection.
Macrophages in H polygyrus
In infection of mice with H. polygyrus, macrophage responses are skewed to the M2/AAM phenotype, and populate submucosal granulomas around tissue-encysted larvae (as in the cartoon above). Similarly, RELMα+Ym1+ macrophages proliferate and expand in the peritoneal cavity over ther first 7 days of H. polygyrus infection (Jenkins et al., 2012 ) In susceptible mouse strains such as C57BL/6, larvae grow in the submucosa over 7-8 days and then remigrate as adults back to the intestinal lumen. More resistant strains (BALB/c and SJL) show a stronger granulomatous response with greater effects on larvae which are either trapped in the granuloma, or emerge with reduced fitness and are expelled quickly from the lumen (data from Filbey et al., 2014)
When primary H. polygyrus infections are cleared by drug treatment, mice then display potent immunity to reinfection: this was shown by Anthony et al (2006) ) to depend on the macrophage response as depletion with clodronate abrogated resistance, as did administration of an inhibitor of arginase enzymatic activity. Similarly, clodronate treatment impairs granuloma formation around tissue larvae in BALB/c and SJL mice, with an overall reduction in their ability to expel the worms (Filbey et al., 2014).
Subsequently, the Voehringer lab showed that STAT6 activated macrophages are in isolation insufficient, with epithelial STAT6 signalling also required for expulsion; these authors also showed that in secondary immunity, Arginase-1 was no longer essential indicating multiple redundant mechanisms at play (Westermann 2023).
How do macrophages attack H. polygyrus?
In primary infection Arginase-1 may deplete the environment of this essential amino acid so depriving it from parasites during their growth phase. However, for potent immunity antibody-mediated mechanisms are required, as B-cell deficient mice were unable to clear the worm.: Macrophage activation is promoted by helminth-specific antibodies leading to direct binding to and immobilization of the parasites (Esser-van Bieren et al., 2013; Esser-van Bieren et al., 2015a), with the same phenotype associated with repair of epithelial lesions caused by worm migration (Esser van Bieren et al., 2015b). When mice vaccinated with HES are infected, there is a 4-fold increase in myeloid cell infiltration into infected submucosal tissue, with subsequent trapping of larvae that are unable to return to the lumen (Hewitson et al., 2015).
To expel luminal adult parasites, the host increases fluid and mucus egress into the intestinal tract, while accelerating peristalsis through smooth muscle hypercontractility – which together with constitutes the “weep-and-sweep” response: this process is dependent on signalling to the enteric nervous system by immune cells such as AAMs.