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Signaling Pathways Governing Activation of Innate Immune Cells

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Tissue-Specific Cell Signaling

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Abstract

In accordance to their functions, most cells from the innate immune system are equipped with multiple receptors that sense invading pathogens and endogenous danger signals resultant from damaged cells. Recognition of such “alarm signals” triggers complex signaling pathways that involve the recruitment of adapter molecules to the receptors and consequent activation of transducers such as protein kinases. Finally, these cascades culminate in the nuclear translocation of transcription factors that control the expression of inflammatory effector molecules like cytokines, chemokines and enzymes involved in oxidative burst and prostaglandin/leukotriene synthesis. Also, Natural Killer (NK) cells, a particular type of inate immune cells, express multiple activating and inhibitory receptors that act in concert to capacitate them to directly recognize and destroy transformed or viraly infected cells, to secrete cytokines or both. The knowledge on these intricate signaling networks is crucial for the comprehension of the physiopathology of inflammatory diseases as well as for identification of possible therapeutical targets. In this chapter we provide an overview of the transduction cascades triggered following danger sensing by innate immune cells, as well as examples evidencing the impact of their malfunction to human health.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

AICL:

Activation-induced C-type lectin

AIM:

Absent-in-melanoma

Akt:

Protein kinase B

ALR:

AIM-like receptors

AMP:

Adenosine monophosphate

AP-1:

Activator protein 1

ASC:

Apoptosis-associated speck-like protein containing CARD

ATP:

Adenosine triphosphate

BCG:

Bacillus Calmette-Guérin

Bcl:

B cell lymphoma

BDCA:

Blood dendritic cell antigen

BIR:

Baculovirus inhibitor repeat

c-Abl:

Abelson tyrosine kinase

CARD:

Caspase recruitment domain protein

CBP:

CREB-binding protein

CCL:

C-C motif chemokine ligand

CD:

Cluster of differentiation

Cdc42:

Cell division cycle 42

cGAMP:

Cyclic-GMP-AMP

cGAS:

cGAMP synthase

CLEC:

C-type lectin-like receptors

CLR:

C-type lectin receptors

CpG ODN:

CpG oligodeoxynucleotides

CRACC:

CD2-like receptor activating cytotoxic cells

CRD:

Carbohydrate recognition domain

CREB:

cAMP response element binding

CTLD:

C-type lectin-like domain

DAI:

DNA-dependent activator of interferon-regulatory factors

DAMPs:

Damage-associated molecular patterns

DAP10, 12:

DNAX activating proteins of 10 kDa, 12 kDa

DC:

Dendritic cell

DCAL-2:

Dendritic cell-associated C-type lectin 2

DCIR:

DC-immunoreceptor

DC-SIGN:

DC-specific intercellular adhesion molecule (ICAM)-3 grabbing nonintegrin

DDX:

DEAD-box helicase 41

DDX60:

DExD/H-box helicase 60

Dectin:

DC-associated C-type lectin-1

DHX:

DExH-box helicase 9

DHX36:

DEAH-box helicase 36

DNA:

Deoxyribonucleic acid

DNAM-1:

DNAX accessory molecule-1

DNAPK:

DNA-dependent protein kinase

dsDNA:

Double stranded DNA

dsRNA:

Double stranded RNA

EAT-2:

Ewing’s sarcoma-associated transcript-2

EBV:

Epstein-Barr vírus

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

FADD:

Fas-associated protein with death domain

FcRγ:

Fc receptor γ chain

GM-CSF:

Granulocyte and macrophage colony stimulating factor

GMP:

Guanosine monophosphate

Grb2:

Growth factor receptor-bound protein 2

HIN:

Hematopoietic interferon-inducible nuclear antigens

HIV-1:

Human immunodeficiency virus 1

HLA:

Human leukocyte antigen

HMGB1:

High-mobility group box 1

hMGL:

Human Monoglyceride lipase

HMGN1:

High Mobility Group Nucleosome Binding Domain 1

HSPs:

Heat-shock proteins

ICAM:

Intercellular adhesion molecule

iE-DAP:

γ-D-glutamyl-meso-diaminopimelic acid

IFI16:

IFN-inducible 16

IFN:

Interferon

IgG:

Immunoglobulin G

IKK:

IκB kinase complex

IL:

Interleukin

ILCs:

Innate lymphoid cells

IRAK:

IL-1 receptor-associated kinase protein

IRF:

Interferon regulatory factor

IRp60:

Inhibitory receptor protein

ISG:

IFN-inducible gene

ITAM:

Immunoreceptor tyrosine-based activation motif

ITIM:

Immunoreceptor tyrosine-based inhibitory motifs

ITSM:

Immunoreceptor tyrosine-based switch motifs

IκB:

Inhibitor of nuclear factor kappa B

JNK:

Jun N-terminal kinase

KACL:

Keratinocyte-associated C-type lectin

KIR:

Killer cell immunoglobulin-like receptor

KLRG1:

Killer cell lectin-like receptor G1

LDL:

Low-density lipoproteins

LFA:

Lymphocyte function associated antigen

LIR:

Leukocyte inhibitory receptor

LMW:

Low molecular weight

LOX-1:

Lectin-like oxidized LDL receptor-1

LPG2:

Laboratory of genetics and physiology 2

LPS:

Lipopolysaccharide

LRR:

Leucine-rich repeat

MAL:

MyD88-adaptor-like

MALT:

Mucosa associated lymphoid tissue translocation protein

MAPK:

Mitogen-activated protein kinase

MAVS:

Mitochondrial antiviral signalling protein

MCL:

Macrophage C-type lectin

MDA5:

Melanoma differentiation-associated gene 5

MDL-1:

Myeloid DAP12-associating lectin

MDP:

Muramyl dipeptide

MEK:

MAPK/ERK kinase

MHC:

Major histocompatibility complex

MICA:

MHC class I chain-related A chain

MICB:

MHC class I chain-related B chain

MICL:

Myeloid inhibitory C-type lectin-like receptor

Mincle:

Macrophage-inducible C-type lectin

MIP:

Macrophage inflammatory protein

MNDA:

Myeloid cell nuclear differentiation antigen

MR:

Mannose receptor

MRE11:

Meiotic recombination 11 homolog A

MTOC:

Microtubule organizing centre

mTOR:

Mechanistic target of rapamycin

MyD88:

Myeloid differentiation primary response gene 88

NAIP:

NLR family, apoptosis inhibitory protein

Nck:

Non-catalytic region of tyrosine kinase adaptor protein 1

ND:

Not determined

NFAT:

Nuclear factor of activated T-cells

NF-κB:

Nuclear factor-kappa B

NIK:

NF-κB-inducing kinase

NK:

Natural Killer

NKG2D:

Natural Killer group 2D

NKR-P1:

Killer cell lectin-like receptor subfamily B, member 1

NLR:

NOD-like receptors

NLRC:

NOD-like receptor family CARD domain containing

NLRP:

Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing

NOD:

Nucleotide-oligomerization domain

NTB-A:

NK, T and B cell antigen

PAMPs:

Pathogen-associated molecular patterns

PI3K:

Phosphoinositide 3-kinase

PLC-γ:

Phospholipase C gamma

PRRs:

Pattern-recognition receptors

PYD:

Pyrin

PYHIN1:

Pyrin and HIN domain-containing protein

Rac-1:

Ras-related C3 botulinum toxin substrate 1

RANTES:

Regulated upon activation, normal T-cell expressed, and secreted

RICK:

RIP-like interacting CLARP kinase

RIG-1:

Retinoic acid-inducible gene-1

RIP-1:

Receptor interacting kinase 1

RLR:

RIG-1-like receptors

RNA:

Ribonucleic acid

ROS:

Reactive oxygen species

SAP:

SLAM-associated protein

SECTM1:

Secreted and transmembrane 1

SH2:

Src homology 2

SHIP-1:

SH2 domain-containing inositol 5′ phosphatase-1

SHP:

Src homology 2 (SH2) domain-containing phosphatases

SIGNR1:

Specific ICAM-3 grabbing nonintegrin-related 1

SLAM:

Signaling lymphocytic activating molecule

SLP-76:

SH2 domain containing leukocyte phosphoprotein of 76 kD

ssRNA:

Single-stranded RNA

STING:

Stimulator of interferon genes

Syk:

Spleen tyrosine kinase

TAB:

TAK1 binding protein

TAK1:

TGF-beta-activated kinase 1

TBK1:

TANK binding kinase 1

TCR:

T cell receptor

TGF:

Transforming growth factor

TICAM:

TIR-domain containing adaptor molecule

TIR:

Toll/IL-1R homology

TIRAP:

TIR-containing adaptor protein

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNFR:

Tumor necrosis factor receptor

TRADD:

TNF receptor-associated death domain

TRAF:

TNFR-associated factor 6

TRAIL:

TNF-related apoptosis-inducing ligand

TRAM:

TRIF-related adaptor molecule

TRIF:

TIR-containing adaptor inducing IFN-β

ULBP:

UL-16 binding protein

WAS:

Wiskott-Aldrich syndrome

WASP:

Wiskott-Aldrich syndrome protein

WIPF1:

WAS/WASL interacting protein family member 1

XLP:

X-linked lymphoproliferative disease

ZAP70:

Zeta-chain-associated protein kinase 70

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Authors and Affiliations

  1. Department of Medical Sciences, iBiMED—Institute for Biomedicine, University of Aveiro, Aveiro, Portugal

    Bruno M. Neves & Catarina R. Almeida

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  1. Bruno M. Neves
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  2. Catarina R. Almeida
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Correspondence to Bruno M. Neves or Catarina R. Almeida .

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  1. Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine—iBiMED, University of Aveiro, Aveiro, Portugal

    Joana Vieira Silva

  2. Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, Belgium

    Maria João Freitas

  3. Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine—iBiMED, University of Aveiro, Aveiro, Portugal

    Margarida Fardilha

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Neves, B.M., Almeida, C.R. (2020). Signaling Pathways Governing Activation of Innate Immune Cells. In: Silva, J.V., Freitas, M.J., Fardilha, M. (eds) Tissue-Specific Cell Signaling. Springer, Cham. https://doi.org/10.1007/978-3-030-44436-5_4

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