Flexible Signaling of Myeloid C-Type Lectin Receptors in Immunity and Inflammation

Abstract

Myeloid C-type lectin receptors (CLRs) are important sensors of self and non-self that work in concert with other pattern recognition receptors (PRRs). CLRs have been previously classified based on their signaling motifs as activating or inhibitory receptors. However, specific features of the ligand binding process may result in distinct signaling through a single motif, resulting in the triggering of non-canonical pathways. In addition, CLR ligands are frequently exposed in complex structures that simultaneously bind different CLRs and other PRRs, which lead to integration of heterologous signaling among diverse receptors. Herein, we will review how sensing by myeloid CLRs and crosstalk with heterologous receptors is modulated by many factors affecting their signaling and resulting in differential outcomes for immunity and inflammation. Finding common features among those flexible responses initiated by diverse CLR-ligand partners will help to harness CLR function in immunity and inflammation.

Keywords: dendritic cells; inflammation; innate immunity; lectin receptors; macrophages; monocytes; signaling.

Figure 1

Canonical signaling modules in myeloid C-type lectin receptors (CLRs). Based on canonical intracellular signaling motifs, myeloid CLRs can be classified into immunoreceptor tyrosine-based activating motif (ITAM)-coupled CLRs, hemi-ITAM-(hemITAM)-bearing CLRs, immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing CLRs, and a group of CLRs lacking typical signaling motifs. Mincle, Dectin-1, DCIR, DC-SIGN, and their corresponding canonical signaling pathways and adaptors are depicted as prototypical examples of each category.

Figure 2

Signaling flexibility downstream of C-type lectin receptors (CLRs). Signaling triggered downstream of CLRs goes beyond the canonical modules present in their intracellular domains and can be modulated by different processes. Some examples of such plasticity are represented. (A) DNGR-1 promotes cross-presentation of antigens to CD8⁺ T cells, yet not directly contributing to inflammation. (B) Mincle and MCL dimerize, boosting phagocytosis, and spleen tyrosine kinase (Syk)-mediated inflammatory responses. (C) Sensing of a soluble ligand from Leishmania by Mincle triggers an inhibitory immunoreceptor tyrosine-based activating motif conformation downstream of Fc receptor γ (FcRγ), where SHP-1 dampens inflammatory responses triggered by heterologous receptors. (D) The phosphatase SHP-2 acts as a scaffold downstream of Dectin-1 and FcRγ-coupled CLRs, facilitating the recruitment of Syk and its inflammatory signaling. (E) Both self and non-self ligands share signaling pathways downstream of DC-SIGN depending on whether they are mannosylated or fucosylated glucans.

Figure 3

Signaling crosstalk between myeloid C-type lectins and heterologous receptors. Signaling pathways initiated downstream of C-type lectin receptors (CLRs) interact with surrounding cascades triggered by heterologous receptors. Examples of such crosstalk are illustrated. (A) Dectin-1 coordinates with simultaneous signals from diverse TLRs to modulate the inflammatory response; this interaction can be either positive, as for TLR2/MyD88 (left), or negative, as for TLR9 through a Pyk2/ERK/SOCS-1-dependent pathway (right). (B) In addition, the axis Dectin-1/PI3K/mTOR/Hif-1α generates a switch toward glycolytic metabolism together with an epigenetic footprint, allowing for a “deferred” improved response to TLRs, boosting the inflammatory response. This process is known as trained immunity. (C) A full inflammatory response against Fonsecaea pedrosoi is achieved by synergistic stimulation between Mincle and ligands for TLRs coupled to the MyD88 adaptor (left). However, simultaneous recognition of Fonsecaea monophora by Mincle and Dectin-1 triggers a Mincle-PKB-Mdm2-dependent degradation of Dectin-1-activated IRF1, dampening the expression of protective IL-12p35 (right). (D) DC-SIGN recognition of Fasciola hepatica enhances TLR-induced IL-10 and IL-27p28 (left). Moreover, DC-SIGN sensing of the salivary protein Salp15 from the tick vector Ixodes scapularis dampens inflammatory responses triggered by Borrelia burgdorferi through TLRs (right). Both examples illustrate strategies to escape immune surveillance based on inhibition of T cell proliferation.