Table 2 Intracellular inhibitors regulating PRR function

A20

Ubiquitinates/deubiquitinates molecules in PRR and TNFR pathways^{92, 93, 94, 95}

Deficiency:

• death due to severe multi-organ inflammation⁹¹

•↑endotoxin shock⁹¹

• deficiency in DCs → colitis⁹⁶

SNPs in the A20 region associated with CD,⁹⁷ SLE^{98, 99} and RA^{100, 101}

ABIN1

Recruits A20^{323, 324}

• dysfunction→ SLE and autoimmunity in mice^{325, 326}

•↑expression protects from TNF-induced death and allergic airway inflammation^{327, 328}

SNPs in ABIN1 region associated with SLE^{329, 330}

ABIN3

• inhibits NF-κB activation³³¹

• binds A20³³¹

adenoviral expression in mice protects from LPS -induced death³³¹

FLN29

• inhibits TRAF6-mediated NF-κB signaling³³²

• inhibits the Rig I pathway³³³

FLN29^−/− →↑endotoxin shock³³³

IRAK-M

Inhibits IRAK-1 activation⁶⁰

Deficiency:

•↑inflammation to microbes⁶⁰

•↑lung injury⁶⁴

•↑IL-10^−/− colitis⁶⁵

• endotoxin tolerance defect⁶⁰

Mutations↑risk for asthma;^{66, 67} dysregulated levels seen in necrotizing enterocolitis,⁶⁸ TB⁶⁹ and cystic fibrosis⁶²

IRF4

↓’s signaling through RIP2¹⁰² and MyD88¹⁰³

• IRF4^−/− →↑DNA shock¹⁰³

• IRF4 knockdown in vivo →↑experimental colitis¹⁰²

↑ expression in mucosa of IBD patients¹⁰⁵

ITAM

Induces inhibitors, including SOCS-1, ABIN-3, A20, and IL-10¹¹²

ITAM-containing receptors suppress inflammatory diseases, including colitis^{113, 114}

MKP-1

Inhibits MAPK signaling³³⁴

Deficiency:

•IL-10^−/− colitis³³⁵

•sepsis due to impaired bacterial killing^{334, 336}

Impaired induction in:

• alveolar macrophages from asthma patients³³⁷

• LPS-treated BAL cells from sarcoidosis patients³³⁸

MyD88s

Prevents MyD88 signaling by failure to recruit IRAK-4³³⁹

•↑in monocytes during sepsis³¹⁷

NLRP12

• inhibits IRAK1 phosphorylation¹⁹⁵

• ↓’s NIK expression¹⁹⁴

Deficiency:

•↑DSS colitis and colitis-associated cancer³⁴⁰

•↑Y. pestis susceptibility¹⁹³

Mutations → auto-inflammatory diseases^{198, 199} and atopic dermatitis²⁰⁰

PGE

• induces IRAK-M³⁴¹

•↓phagocytosis, bacterial killing^{342, 343}

Mice with prostaglandin pathway deficiency →↑colitis and colonic injury^{344, 345}

SNPs in a region that includes PTGER4 associated with IBD¹⁰

SHIP-1

• dephosphorylates TBK1 and inhibits IFNβ induction¹⁰⁶

• inhibits PI3K signaling¹⁰⁷

Deficiency:

• ileitis¹⁰⁹

• endotoxin tolerance defect¹⁰⁷

• macrophage infiltration in bone marrow and spleen¹¹⁰

•↓life span¹¹⁰

↑ SHIP-1 expression in the intestinal mucosa of IBD patients¹¹¹

SOCS-1

Inhibits JAK/STAT signaling^{70, 71, 72}

Deficiency ↑’s inflammatory cytokine production and endotoxin shock^{72, 346}

Loss-of-function/expression SNPs:↑serum IgE⁷⁸ and↑asthma⁷⁹ and lymphoma³⁴⁷

SOCS-3

Inhibits STAT1 and STAT3 activation^{348, 349}

• deficiency → embryonic lethality³⁵⁰

• deficiency in macrophages→↑endotoxin shock³⁵¹

↑ SOCS-3 expression in mucosal biopsies from CD patients³⁵²

TOLLIP

• associates with TLR2 and TLR4 to limit signaling^{353, 354}

• inhibits IRAK-1 signaling^{354, 355}

Deficiency→↑inflammation following sublethal endotoxin³⁵⁶

SNPs associated with atopic dermatitis³⁵⁷ and SNPs with decreased Tollip mRNA associated with TB³⁵⁸

TWIST family

• Twist1 and Twist2 inhibit NF-κB p65 transactivation³⁵⁹

• Twist1 and Twist2 repress the TNF-α gene promoter⁸²

• Twist2 induces IL-10 through c-Maf activation³⁶⁰

• Twist1^−/−: embryonic death³⁶¹

• Twist2^−/−:

→perinatal death with

cachexia and↑cytokines³⁵⁹

→endotoxin tolerance defect

in macrophages³⁶⁰

•↑Twist1 expression in Th1 lymphocytes in inflamed tissue from IBD and RA patients³⁶²

TAM receptors

• SOCS-1 and -3 induction⁸⁰

• apoptotic cell clearance^{85, 86, 87}

Deficiency/functional defect:

• SLE and autoimmunity^{81, 85}

•↑endotoxin shock⁸³

TAM receptor ligand levels dysregulated in SLE and UC^{89, 90}