TABLE 2.

Effects of ibrutinib and acalabrutinib on monocytes and macrophages.

Cells	Inhibitor	Target	Signaling pathway	Effects	References
Monocytes	Acalabrutinib	BTK	TLR9/TREM-1/Dectin-1-BTK	Inhibits TNF-α and IL-1β production and phagocytosis during Aspergillus fumigatus infection or stimulation with zymosan	Fiorcari et al., 2020
			TLR7/8-MyD88-BTK	Reduces IL-6 production in monocytes of COVID-19 patients	Roschewski et al., 2020
	Ibrutinib		Unclear	Progressively increases circulating monocyte counts in CLL patients	Solman et al., 2020, 2021
				Reduces the refractory state of monocytes in CLL patients	Cubillos-Zapata et al., 2016
				Restores LPS-induced inflammatory responses in monocytes of CLL patients	Cubillos-Zapata et al., 2016
				Enhances HLA-DR expression on monocytes in CLL patients after long-term administration	Manukyan et al., 2018
			FPR-BTK?	Inhibits chemoattractant-triggered inside-out signaling of β2 integrins (LFA-1 and Mac1) and thus adhesion to ICAM-1	Ferrarini et al., 2019
			LFA-1/Mac1-BTK?	Inhibits β2 integrin-mediated outside-in signaling and thus spreading on ICAM-1	Ferrarini et al., 2019
			M-CSFR-BTK/TEC?	Alters M-CSF-induced differentiation to fibrocyte- like cells with defective adhesion, impaired phagocytosis and enhanced ROS production	Ferrarini et al., 2019
		BTK	TLR9/TREM-1/Dectin-1-BTK	Inhibits TNF-α and IL-1β production and phagocytosis during Aspergillus fumigatus infection or stimulation with zymosan	Fiorcari et al., 2020
			NLRP3-BTK-PP2A	Enhances inflammasome activity in monocytes of CLL patients that received ibrutinib treatment	Mao et al., 2020
			α4β1-PI3Kγ-BTK-PLCγ2	Inhibits integrin activation and SDF1- or IL1β-mediated adhesion to VCAM1	Gunderson et al., 2016
			FcRγ-SYK-BTK-PLCγ2	Inhibits FcγR-mediated cytokine production	Ren et al., 2016
Macrophages	Acalabrutinib	BTK	TLR-MyD88-BTK-NF-κB	Suppresses LPS-induced MCP-1 production and macrophage infiltration	Shaker et al., 2020
			TLR9/TREM-1/Dectin-1-BTK	Inhibits TNF-α and IL-1β production and phagocytosis during Aspergillus fumigatus infection or stimulation with zymosan	Fiorcari et al., 2020
			TLR-NLPR3-BTK-NFκB	Reduces cytokine and chemokine production Attenuates sepsis-associated cardiac dysfunction in mice	O’Riordan et al., 2019
			None	Does not impair ADCP of rituximab-opsonized CLL cells	Golay et al., 2017; VanDerMeid et al., 2018
			FcγR-BTK?	Weakly inhibits ADCP of CLL cells opsonized with ofatumumab and ocaratuzumab	VanDerMeid et al., 2018
	Ibrutinib	BTK	TLR-MyD88-BTK-NF-κB/IRFs/STAT3/AP-1	Suppresses TLR-induced cytokine and chemokine production	Niemann et al., 2016; Ping et al., 2017
			TLR4-MyD88-BTK-STAT1	Sustains the M2 phenotypes and immunosuppressive profile of NLCs	Fiorcari et al., 2016
			TLR-BTK-calreticulin	Inhibits TLR-mediated phagocytosis of tumor cells	Feng et al., 2015
			TLR9-MyD88-BTK-NF-κB/NFATc1	Inhibits TNFα production and phagocytosis during fungal infection	Bercusson et al., 2018
			TLR9/TREM-1/Dectin-1- BTK	Inhibits TNF-α and IL-1β production and phagocytosis during Aspergillus fumigatus infection or stimulation with zymosan	Fiorcari et al., 2020
			NLRP3-ASC-BTK-NF-κB/caspase-1	Suppresses NLRP3-mediated inflammasome activation and blocks IL-1β processing	Ito et al., 2015; Liu et al., 2017,Benner et al., 2019
				Protects against ischemic brain injury by inhibiting NLRP3-mediated inflammasome activation	Ito et al., 2015
			NLRP3-BTK-PP2A	Enhances inflammasome activity by low doses of ibrutinib	Mao et al., 2020
			TLR-NLPR3-BTK-NF-κB	Reduces cytokine and chemokine production, affects bacterial clearance, and attenuates sepsis-associated cardiac dysfunction in mice	Benner et al., 2019; O’Riordan et al., 2019,Liu et al., 2017; de Porto et al., 2019
			α4β1-PI3Kγ-BTK-PLCγ2	Inhibits integrin activation and SDF1- or IL1β-mediated adhesion to VCAM1	Gunderson et al., 2016
			BTK-PKCβ-AKT-mTOR-ATG/LC3b/p62	Induces autophagy of M. tuberculosis and suppresses Mtb intracellular growth	Hu et al., 2020
			FcRγ-SYK-BTK-PLCγ2	Promotes macrophage M1 polarization and inhibits macrophage M2 polarization	Gunderson et al., 2016
		TEC?	FcγR-TEC family?	Impairs ADCP of rituximab-opsonized CLL cells by human macrophages	Borge et al., 2015; Da Roit et al., 2015
					Golay et al., 2017; VanDerMeid et al., 2018
			FcγR-TEC/BTK?	Inhibits ADCP of CLL cells opsonized with ofatumumab and ocaratuzumab	VanDerMeid et al., 2018
		JAK2	FcγR-JAK2-STAT3/6	Enhances ADCP of opsonized MYC/BCL2 cells by mouse macrophage cell line J774A.1 cells	Barbarino et al., 2020