β‐Glucan receptors on IL‐4 activated macrophages are required for hookworm larvae recognition and trapping

Abstract

Recent advances in the field of host immunity against parasitic nematodes have revealed the importance of macrophages in trapping tissue migratory larvae. Protective immune mechanisms against the rodent hookworm Nippostrongylus brasiliensis (Nb) are mediated, at least in part, by IL-4-activated macrophages that bind and trap larvae in the lung. However, it is still not clear how host macrophages recognize the parasite. An in vitro co-culture system of bone marrow-derived macrophages and Nb infective larvae was utilized to screen for the possible ligand-receptor pair involved in macrophage attack of larvae. Competitive binding assays revealed an important role for b-glucan recognition in the process. We further identified a role for CD11b and the non-classical pattern recognition receptor ephrin-A2 (EphA2), but not the highly expressed b-glucan dectin-1 receptor, in this process of recognition. This work raises the possibility that parasitic nematodes synthesize b-glucans and it identifies CD11b and ephrin-A2 as important pattern recognition receptors involved in the host recognition of these evolutionary old pathogens. To our knowledge, this is the first time that EphA2 has been implicated in immune responses to a helminth.

Holding glycolysis in check though Alox15 activity is required for macrophage M2 commitment and function in tissue repair and anti-helminth immunity

“…First, we polarized bone marrow derived macrophages with M2 or M1 stimulants (IL-4, IL-13, LPS and IFNγ) and then co-cultured these cells with Nb. As previously described [34], ‘M0’ macrophages can to some extent bind to Nb larvae and IL-4 polarization enhances this binding (Figure 6a). Interestingly, the reduced binding of Alox15-/-macrophages was not observed when cells were stimulated with IL-13 alone or IL-13 together with IL-4, suggesting IL-13 polarisation might be Alox15-independent.…”

“…Macrophages are central to anti-helminth immunity in the vast majority of mouse models but are largely unstudied in human helminthiasis. In rodents, macrophages require a so-called ‘alternative’ or “M2” activation mediated by type 2 cytokines or antibodies [4–6, 29, 34]. This M2 signature is also enhanced by collectins and stress signals [25, 30].…”

CLEC4A and CLEC12B C-type lectin receptors mediate interactions with Pneumocystis cell wall components

“…Both curdlan and laminarin are also known to contain GlcNac residues [39–41]. Dextran, consisting of α−1,6 linkages with branched α−1,3 side chains [42] was used as a negative control as previously reported [33]. We determined that both CLEC4A and CLEC12B CLR fusions significantly bound to both curdlan and laminarin preparations (), but dextran failed to bind either CLR fusion protein to significant levels ().…”

“…Sugar binding assays were performed with immobilized curdlan and laminarin (2.0 ug per well each), with both ligands known to possess 1,3-β-glucan linkages as well as GlcNac. For contrast, we also tested dextran, a complexed branched glucan with predominantly 1,6-linkages and lacking GlcNAc [33,34].…”

How to train your myeloid cells: a way forward for helminth vaccines?

“…Whether or not β-glucans are specifically, which have been shown to induce trained immunity, produced by helminths is not formally proven. However, we have recently demonstrated that laminarin supplementation competitively inhibits the binding of macrophages to N. brasiliensis larvae in a pathway dependent on CD11b or the β-glucan receptor Eph2A ( 213 ). Another β-glucan receptor, dectin-1, has also been shown to be important for the recognition of egg antigens from S. mansoni and triggers the release of ETs in response to microfilariae.…”