Multiple negative regulatory mechanisms operate at molecular levels: (i) A20 dampens NF-κB signaling through deubiquitination of key intermediates like TRAF6 (37); (ii) suppressors of cytokine signaling (SOCS) proteins terminate TLRs responses by blocking janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways and promoting signalosome degradation (38); (iii) aberrant recognition of endogenous ligands (e.g., heat shock proteins, high mobility group box 1 [HMGB1], and self-DNA) may break immune tolerance, particularly evidenced in autoimmune diseases like SLE (39). Here, HMGB1 is linked to systemic lupus erythematosus.