Abstract: Cluster of differentiation 74 (CD74), also called as major histocompatibility complex class II (MHCII) invariant chain, is involved in trafficking MHCII cell surface molecules on antigen-presenting cells and has been implicated in many signaling pathways. For example, the interaction between CD74 and macrophage migration inhibitory factor cytokine (MIF) leads to the activation of a plethora of pathways such as extracellular regulated protein kinases, phosphoinositide 3-kinase, and nuclear factor-κB which are essential for cell survival, differentiation, and proliferation. Structurally, CD74 is a type 2 transmembrane receptor with a short N-terminal cytoplasmic tail consisting of 28 amino acids, a 24-amino acid transmembrane region, and a luminal domain of approximately 150 amino acids. In mice, Cd74 occurs in two isoforms, namely p31, and p41, due to alternative splicing. In humans, along with the p33 and p41 isoforms that correspond to the p31 and p41 isoforms of mice, two additional isoforms p35 and p43 can also be found (Farr et al., 2020). Microglia are central nervous system (CNS)-specific antigen-presenting cells with diverse functional repertoire. Microglia remain in a resting, albeit a surveying state under normal physiological conditions. Such microglia are deemed to be in their homeostatic state with a characteristic expression of Tmem119, Olfml3, P2ry12, Sall1, Hexb, Gpr34, or Fcrls. They however become reactive under pathological states assuming phenotypes with increased expression of genes such as ApoE, Axl, Clec7a, Cst7, Cybb, and Ctsb. It is now widely accepted that this microglial activation and the resultant dysregulation is an inevitable component of almost all CNS pathologies (Pettas et al., 2022).